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Τρίτη 23 Μαΐου 2017

A mutation in GABRB3 associated with Dravet syndrome

Dravet syndrome is a rare and severe type of epilepsy in infants. Approximately, 70–80% of patients with Dravet syndrome have mutations in SCN1A, the gene encoding the alpha-1 subunit of the sodium channel, while some simplex patients have variants in one of several other genes, including but not limited to GABRA1, SCN2A, STXBP1, GABRG2, and SCN1B. In this study, we performed exome sequencing in six patients with SCN1A-negative Dravet syndrome to identify other genes related to this disorder. In one affected individual, we detected a novel de novo heterozygous missense variant, c.695G>A, p.(Arg232Gln), in GABRB3, the gene encoding the β3-subunit of the gamma-aminobutyric acid type A (GABAA) receptor, which mediates inhibitory signaling within the central nervous system. In summary, the data in this study identify GABRB3 as a candidate gene for Dravet syndrome.



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37th Annual David W. Smith Workshop on Malformations and Morphogenesis: Abstracts of the 2016 Annual Meeting

The 37th Annual David W. Smith Workshop on Malformations and Morphogenesis occurred on September 9th–14th, 2016 at the University of California—Los Angeles Conference Center in Lake Arrowhead, CA. The Workshop, which honors the legacy of David W. Smith, brought together clinicians and researchers interested in congenital malformations and their underlying mechanisms of morphogenesis. The Workshop highlighted five themes besides mechanisms of morphogenesis and New Syndromes: Neural Crestopathies, Mosaicism, Disorders of Skin Pigmentation, Therapies, and Ear Malformations and Hearing Loss. This Conference Report includes the abstracts presented at the 2016 Workshop.



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Discordant phenotypes in monozygotic twins with 16p11.2 microdeletions including the SH2B1 gene

A 200∼240 kb SH2B1-containing deletion region on 16p11.2 is associated with early-onset obesity and developmental delay. Here, we describe monozygotic twin brothers with discordant clinical presentations. Intrauterine fetal growth restriction was present in both twins. Additionally, twin A exhibited coarctation of aorta, left ventricular noncompaction, atrial septal defect, pericardial effusion, left hydronephrosis, and moderate developmental delay, whereas twin B exhibited single umbilical artery. Chromosome microarray analysis was performed on both twins and their parents. An identical 244 kb microdeletion on 16p11.2 including 9 Refseq genes, including SH2B1, was identified in the twins. The novel findings in monozygotic twins may expand the phenotypic spectrum of 16p11.2 microdeletion. Further studies are needed to strengthen the correlation between genotypes and abnormal clinical features.



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Obstructive sleep apnea in Down syndrome: Benefits of surgery and noninvasive respiratory support

Children with Down syndrome are at increased risk of obstructive sleep apnea (OSA). The aim of the study was to describe the management of OSA in a large cohort of children with Down syndrome. A retrospective analysis of sleep studies and consequent management was performed for all consecutive Down syndrome patients evaluated between September 2013 and April 2016. The data of 57 patients were analyzed: 51/53 had an interpretable overnight polygraphy and 4 the recording of nocturnal gas exchange. Mean age at baseline sleep study was 6.2 ± 5.9 years. Eighteen patients (32%) had prior upper airway surgery. Mean apnea-hypopnea index (AHI) was 14 ± 16 events/hr with 41 of the 51 (80%) patients having OSA with an AHI >1 event/hr and 20 patients (39%) having an AHI ≥10 events/hr. Consequently, eight patients (14%) had upper airway surgery. OSA improved in all patients except two who needed noninvasive respiratory support. Nineteen (33%) patients required noninvasive respiratory support. Mean age at noninvasive respiratory support initiation was 7 ± 7 years. On 11 patients with objective adherence data available, mean compliance at 2 ± 1 years of treatment was excellent with an average use per night of 8 hr46 ± 3 hr59 and 9 patients using the noninvasive respiratory support >4 hr/night. Noninvasive respiratory support was associated with an improvement of nocturnal gas exchange. The prevalence of OSA is high in Down syndrome. Upper airway surgery is not always able to correct OSA. Noninvasive respiratory support represents then an effective treatment for OSA and good compliance may be achieved in a majority of patients.



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Haploinsufficiency of NR4A2 is associated with a neurodevelopmental phenotype with prominent language impairment

Non-recurrent deletions in 2q24.1, minimally overlapping two genes, NR4A2 and GPD2, were recently described in individuals with language impairment and behavioral and cognitive symptoms. We herewith report on a female patient with a similar phenotype of severe language and mild cognitive impairment, in whom we identified a de novo deletion covering only NR4A2. NR4A2 encodes a transcription factor highly expressed in brain regions critical for speech and language and implicated in dopaminergic neuronal development. Our findings of a de novo deletion of NR4A2 in an individual with mild intellectual disability and prominent speech and language impairment provides further evidence for NR4A2 haploinsufficiency being causative for neurodevelopmental and particularly language phenotypes.



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Viruses and endogenous retroviruses in multiple sclerosis: From correlation to causation

Multiple sclerosis is an immune-mediated disease with an environmental component. According to a long-standing but unproven hypothesis dating to initial descriptions of multiple sclerosis (MS) at the end of the 19th century, viruses are either directly or indirectly implicated in MS pathogenesis. Whether viruses in MS are principally causal or simply contributory remains to be proven, but many viruses or viral elements—predominantly Epstein-Barr virus, human endogenous retroviruses (HERVs) and human herpesvirus 6 (HHV-6) but also less common viruses such as Saffold and measles viruses—are associated with MS. Here, we present an up-to-date and comprehensive review of the main candidate viruses implicated in MS pathogenesis and summarize how these viruses might cause or lead to the hallmark demyelinating and inflammatory lesions of MS. We review data from epidemiological, animal and in vitro studies and in doing so offer a transdisciplinary approach to the topic. We argue that it is crucially important not to interpret "absence of evidence" as "evidence of absence" and that future studies need to focus on distinguishing correlative from causative associations. Progress in the MS-virus field is expected to arise from an increasing body of knowledge on the interplay between viruses and HERVs in MS. Such interactions suggest common HERV-mediated pathways downstream of viral infection that cause both neuroinflammation and neurodegeneration. We also comment on the limitations of existing studies and provide future research directions for the field.



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3D Bioprinting Human Induced Pluripotent Stem Cell Constructs for In Situ Cell Proliferation and Successive Multilineage Differentiation

The ability to create 3D tissues from induced pluripotent stem cells (iPSCs) is poised to revolutionize stem cell research and regenerative medicine, including individualized, patient-specific stem cell-based treatments. There are, however, few examples of tissue engineering using iPSCs. Their culture and differentiation is predominantly planar for monolayer cell support or induction of self-organizing embryoids (EBs) and organoids. Bioprinting iPSCs with advanced biomaterials promises to augment efforts to develop 3D tissues, ideally comprising direct-write printing of cells for encapsulation, proliferation, and differentiation. Here, such a method, employing a clinically amenable polysaccharide-based bioink, is described as the first example of bioprinting human iPSCs for in situ expansion and sequential differentiation. Specifically, There are extrusion printed the bioink including iPSCs, alginate (Al; 5% weight/volume [w/v]), carboxymethyl-chitosan (5% w/v), and agarose (Ag; 1.5% w/v), crosslinked the bioink in calcium chloride for a stable and porous construct, proliferated the iPSCs within the construct and differentiated the same iPSCs into either EBs comprising cells of three germ lineages—endoderm, ectoderm, and mesoderm, or more homogeneous neural tissues containing functional migrating neurons and neuroglia. This defined, scalable, and versatile platform is envisaged being useful in iPSC research and translation for pharmaceuticals development and regenerative medicine.

Thumbnail image of graphical abstract

Human tissues are generated by 3D bioprinting human induced pluripotent stem cells that proliferate and differentiate to form renewable 3D tissues. 3D tissues comprise cells of the three germ lineages—endoderm, ectoderm, and mesoderm, demonstrating the capacity to form all cells and tissues of the body, or more homogeneous neural tissues containing functional (including migrating) neurons and supporting neuroglia.



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Involvement of the DNA mismatch repair system in cisplatin sensitivity of testicular germ cell tumours

Abstract

Background

Testicular germ cell tumours (TGCT) are highly sensitive to cisplatin-based chemotherapy, but patients with tumours containing differentiated teratoma components are less responsive to this treatment. The cisplatin sensitivity in TGCT has previously been linked to the embryonic phenotype in the majority of tumours, although the underlying mechanism largely remains to be elucidated. The aim of this study was to investigate the role of the DNA mismatch repair (MMR) system in the cisplatin sensitivity of TGCT.

Methods

The expression pattern of key MMR proteins, including MSH2, MSH6, MLH1 and PMS2, were investigated during testis development and in the pathogenesis of TGCT, including germ cell neoplasia in situ (GCNIS). The TGCT-derived cell line NTera2 was differentiated using retinoic acid (10 μM, 6 days) after which MMR protein expression and activity, as well as cisplatin sensitivity, were investigated in both undifferentiated and differentiated cells. Finally, the expression of MSH2 was knocked down by siRNA in NTera2 cells after which the effect on cisplatin sensitivity was examined.

Results

MMR proteins were expressed in proliferating cells in the testes, while in malignant germ cells MMR protein expression was found to coincide with the expression of the pluripotency factor OCT4, with no or low expression in the more differentiated yolk sac tumours, choriocarcinomas and teratomas. In differentiated NTera2 cells we found a significantly (p < 0.05) lower expression of the MMR and pluripotency factors, as well as a reduced MMR activity and cisplatin sensitivity, compared to undifferentiated NTera2 cells. Also, we found that partial knockdown of MSH2 expression in undifferentiated NTera2 cells resulted in a significantly (p < 0.001) reduced cisplatin sensitivity.

Conclusion

This study reports, for the first time, expression of the MMR system in fetal gonocytes, from which GCNIS cells are derived. Our findings in primary TGCT specimens and TGCT-derived cells suggest that a reduced sensitivity to cisplatin in differentiated TGCT components could result from a reduced expression of MMR proteins, in particular MSH2 and MLH1, which are involved in the recognition of cisplatin adducts and in activation of the DNA damage response pathway to initiate apoptosis.



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Airway management during induction of anaesthesia, spontaneous ventilation (SV) and controlled mechanical ventilation (CMV), using an endotracheal tube (ETT), laryngeal mask (LM), rabbit-specific supraglottic airway device (v-gel) or facemask (FM).






Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
6948891480

Curcumin attenuates lipopolysaccharide/d-galactosamine-induced acute liver injury

Curcumin, a polyphenol in curry spice isolated from the rhizome of turmeric, has been reported to possess versatile biological properties including anti-inflammatory, anti-oxidant, antifibrotic, and anticancer activities. In this study, the hepatoprotective effect of curcumin was investigated in lipopolysaccharide (LPS)/d-galactosamine (d-GalN)-induced acute liver injury (ALI) in rats. Experimental ALI was induced with an intraperitoneal (ip) injection of sterile 0.9% sodium chloride (NaCl) solution containing 8μg LPS and 800mg/kg d-GalN. Curcumin was administered once daily starting three days prior to LPS/d-GalN treatment. Results indicated that curcumin could attenuate hepatic pathological damage, decrease serum ALT and AST levels, and reduce malondialdehyde (MDA) content in experimental ALI rats. Moreover, higher dosages of curcumin pretreatment inhibited NF-κB activation and reduced serum TNF-α and liver TNF-α levels induced by LPS/d-GalN ip injection. Furthermore, we found that curcumin up-regulated the expression of nuclear Nrf2 and Nrf2-dependent antioxidant defense genes including heme oxygenase-1 (HO-1), glutamate-cysteine ligase (GCLC), NAD(P)H dehydrogenase, and quinone (NQO-1) in a dose-dependent manner. Our results showed that curcumin protected experimental animals against LPS/d-GalN-induced ALI through activation of Nrf2 nuclear translocation and inhibition of NF-κB activation.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
6948891480

Making People Feel Bad Can Be a Strategy for Helping Them

People may try to make someone else feel negative emotions if they think experiencing those emotions will be beneficial in the long run, according to new research published in Psychological Science, a journal of the Association for Psychological Science. The findings expand on previous research by revealing that people may sometimes seek to induce negative emotions in others for altruistic reasons, not simply for their own pleasure or benefit.

"We have shown that people can be 'cruel to be kind'—that is, they may decide to make someone feel worse if this emotion is beneficial for that other person, even if this does not entail any personal benefit for them," explains psychological scientist Belén López-Pérez, who conducted the research while at the University of Plymouth and is currently at Liverpool Hope University. "These results expand our knowledge of the motivations underlying emotion regulation between people."

In other studies, researchers had shown that people may sometimes seek to worsen others' mood for their own personal gain. Based on their own work examining altruistic behavior, López-Pérez and colleagues Laura Howells and Michaela Gummerum wondered whether there might be circumstances under which people would try to worsen others' mood for altruistic reasons.

"We identified several everyday examples where this might be the case—for instance, inducing fear of failure in a loved one who is procrastinating instead of studying for an exam," López-Pérez says.

The researchers hypothesized that prompting participants to take another person's perspective might make them more likely to choose a negative experience for that person if they thought the experience would help the individual reach a specific goal.

To test their hypothesis, they recruited 140 adults to participate in a lab-based study that involved playing a computer game with an anonymous partner, known as Player A. In reality, the participants were always assigned the role of Player B and there was no actual Player A.

After receiving a note supposedly written by Player A, some participants were asked to imagine how Player A felt, while others were told to remain detached. The note described Player A's recent breakup and how upset and helpless Player A felt about it.

Then, participants were asked to play a video game so they could then make decisions for Player A on how the game would be presented. Depending on the experimental condition participants were assigned to, half were asked to play Soldier of Fortune, a first-person shooter game with an explicit goal of killing as many enemies as possible (i.e., confrontation goal). The other half were asked to play Escape Dead Island, a first-person game with the explicit goal of escaping from a room of zombies (i.e., avoidance goal).

After playing the assigned game, the participants listened to some music clips and read short game descriptions that varied in their emotional content. The participants used scales to rate how much they wanted their partner to listen to each clip and read each description (from 1 = not at all to 7 = extremely). They also rated the extent to which they wanted their partner to feel angry, fearful, or neutral and how useful these emotions would be in playing the game.

The players were awarded raffle tickets for a chance at winning £50 based on their performance in the game — participants were reminded that their choices might impact the other participants' performance and, therefore, their own chances of winning the £50.

The results showed that the participants who empathized with Player A focused on inducing specific emotions in their partner, depending on the ultimate goal of their computer game.

Compared with participants who had remained detached, those who empathized with Player A and who played the first-person shooter game seemed to focus specifically on inducing anger in Player A explicitly and implicitly (i.e., by choosing the anger-inducing music clips and game description), while those who had empathized with Player A and who played the zombie game focused specifically on inducing fear (i.e., by choosing the fear-inducing music clips and game description).

"What was surprising was that affect worsening was not random but emotion-specific," says López-Pérez. "In line with previous research, our results have shown that people hold very specific expectations about the effects that certain emotions may have and about which emotions may be better for achieving different goals."

The study suggests that empathy led people to choose particular negative emotional experiences that they believed would ultimately help their partner be successful in the context of the game.

"These findings shed light on social dynamics, helping us to understand, for instance, why we sometimes may try to make our loved ones feel bad if we perceive this emotion to be useful to achieve a goal," López-Pérez concludes.

Michaela Gummerum was partly funded by Economic and Social Research Council Grant ES/K000942/1. Additional funding was provided by the School of Psychology at Plymouth University.



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Randomized Phase 3 Trial of Ombitasvir/Paritaprevir/Ritonavir and Ribavirin for Hepatitis C Virus Genotype 2-Infected Japanese Patients

Abstract

Introduction

In Japan, hepatitis C virus (HCV) genotype (GT) 2 accounts for approximately 32% of HCV infections. Limited treatment options exist in Japan for HCV GT2-infected patients. GIFT-II was a phase 3, randomized, open-label study evaluating the efficacy and safety of 16- and 12-week regimens of co-formulated ombitasvir (OBV)/paritaprevir (PTV)/ritonavir (r) plus ribavirin (RBV) in Japanese adults with HCV GT2 infection.

Methods

Patients were randomized in a 1:1 ratio to once-daily, co-formulated OBV/PTV/r (25/150/100 mg) with weight-based RBV for 16 or 12 weeks. The primary efficacy endpoint was the sustained virologic response at 12 weeks post-treatment (SVR12) rate in the primary efficacy population of non-cirrhotic treatment-naive patients.

Results

A total of 171 patients were randomized to OBV/PTV/r + RBV. In the primary efficacy population, SVR12 rates were 91.5% (43/47; 95% confidence interval 83.5–99.5%) and 75.0% (36/48; 95% confidence interval 62.8–87.2%) in the 16-week arm and 12-week arm, respectively. No patient in the 16-week arm relapsed by post-treatment week 12. Among non-cirrhotic treatment-experienced patients, the overall SVR rate in the 16-week arm was 75.8% (25/33) and was highest [93.8% (15/16)] among those who had relapsed after previous interferon-based therapy. SVR12 rates were consistently higher in patients with HCV GT2a infection versus HCV GT2b infection [16-week treatment arm: 93.9% (31/33) versus 85.7% (12/14) and 93.8% (15/16) versus 56.3% (9/16) among non-cirrhotic treatment-naive and treatment-experienced patients, respectively]. No patient discontinued treatment because of an adverse event. The most common adverse events were anemia, increased blood bilirubin, and nasopharyngitis.

Conclusions

OBV/PTV/r + RBV for 16 weeks resulted in high SVR12 rates in non-cirrhotic Japanese patients infected with HCV GT2 who were treatment-naive or who had relapsed after an interferon-based therapy. Higher SVR12 rates were observed among patients with HCV GT2a infection versus those with GT2b infection. This regimen demonstrated a favorable safety profile.

Trial Registration: ClinicalTrials.gov identifier, NCT02023112.

Funding: AbbVie.



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Study Design of VESUTO ® : Efficacy of Tiotropium/Olodaterol on Lung Hyperinflation, Exercise Capacity, and Physical Activity in Japanese Patients with Chronic Obstructive Pulmonary Disease

Abstract

Introduction

The superiority of tiotropium/olodaterol is demonstrated in improvement of lung function, dyspnea, lung hyperinflation, and quality of life compared with either monotherapy in patients with chronic obstructive pulmonary disease (COPD). Japanese Respiratory Society Guidelines for COPD management include improvement of exercise tolerance and daily physical activity as the treatment goals; however, there is limited evidence in Japanese patients with COPD.

Methods

A protocol is developed for the VESUTO® study that investigates the efficacy of tiotropium/olodaterol fixed-dose combination (FDC) compared with tiotropium alone on inspiratory capacity (IC, volume from functional residual capacity to total lung capacity), exercise capacity, and daily physical activity in Japanese patients with COPD.

Results

A total of 180 Japanese patients with COPD, aged ≥40 years will be enrolled into the double-blind, multicenter, active-controlled, crossover study (NCT02629965) and will be randomized to receive either tiotropium/olodaterol FDC or tiotropium for 6 weeks each [two puffs via RESPIMAT® (Boehringer Ingelheim, Ingelheim, Germany) inhaler in the morning]. The primary endpoint is IC at rest measured at 60 min post-dose after 6 weeks treatment. The secondary endpoints include the 6-min walk distance (6MWD) at 90 min post-dose and physical activity measured by the activity monitor in the last 2 weeks of the 6-week treatment periods. Lung function tests will also be assessed after 6 weeks treatment. A mixed-effects model repeated measures approach will be used for the primary and secondary endpoints.

Conclusion

The VESUTO® study is the first randomized interventional study to investigate exercise capacity (6MWD) and physical activity measured by a 3-axis accelerometer in Japanese patients with COPD. The study could provide additional evidence of long-acting muscarinic antagonist (LAMA) + long-acting β2-agonist (LABA) combination therapy on patients' physical activities as well as lung function.

Trial registration

ClinicalTrials.gov: NCT02629965 (registered on December 1, 2015).

Funding

The VESUTO study was funded by Nippon Boehringer Ingelheim Co., Ltd., Tokyo, Japan.



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Life Impact and Treatment Preferences of Individuals with Asthma and Chronic Obstructive Pulmonary Disease: Results from Qualitative Interviews and Focus Groups

Abstract

Introduction

The impact of asthma and chronic obstructive pulmonary disease (COPD) on individuals' lives may be substantial, yet clinical practice often focuses only on symptoms. We aimed to better understand the perspective of asthma or COPD patients and to identify condition-related burden, life impact, priorities, unmet needs, and treatment goals.

Methods

Individuals aged at least 18 years with asthma or COPD were identified by a recruitment panel via clinical referrals, support groups, consumer networks, and a patient database. Interviews were carried out individually (by telephone) or in focus groups (with no more than five participants per group). A semi-structured interview guide was used with prespecified topics, informed by a literature review, that were considered impactful in asthma or COPD (symptoms and daily-life impact, satisfaction with current treatment, important aspects of treatment, adherence, and ideal treatment).

Results

Overall, 72 people participated in focus groups/individual interviews (asthma n = 18/n = 21; COPD n = 15/n = 18). "Shortness of breath" was the most frequently reported symptom; however, participants discussed the life impact of their condition more than symptoms alone. Reported physical impacts included the inability to sleep and socialize, while emotional impacts included "embarrassment, stigma, and/or self-consciousness", "fear and/or panic", and "sadness, anxiety, and/or depression". Coping mechanisms for normal activities included continuing at reduced pace and avoidance. Treatment preferences centered on resolving impacts; improved sleep, "speed of action", and "length of relief" were the most frequently reported ideal treatment factors.

Conclusion

Patients with asthma or COPD experience substantial quality of life limitations and tend to focus on these in their expressions of concern, rather than symptoms per se. Life impacts of these conditions may have implications beyond those commonly appreciated in routine practice; these considerations will be applied to a future discrete choice experiment survey.

Funding

GSK funded study (H0-15-15502/204821).



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Advances in Clinical Cardiology 2016: A Summary of the Key Clinical Trials

Abstract

Introduction

The findings of many new cardiology clinical trials over the last year have been published or presented at major international meetings. This paper aims to describe and place in context a summary of the key clinical trials in cardiology presented between January and December 2016.

Methods

The authors reviewed clinical trials presented at major cardiology conferences during 2016 including the American College of Cardiology (ACC), European Association for Percutaneous Cardiovascular Interventions (EuroPCR), European Society of Cardiology (ESC), European Association for the Study of Diabetes (EASD), Transcatheter Cardiovascular Therapeutics (TCT), and the American Heart Association (AHA). Selection criteria were trials with a broad relevance to the cardiology community and those with potential to change current practice.

Results

A total of 57 key cardiology clinical trials were identified for inclusion. Here we describe and place in clinical context the key findings of new data relating to interventional and structural cardiology including delayed stenting following primary angioplasty, contrast-induced nephropathy, management of jailed wires, optimal duration of dual antiplatelet therapy (DAPT), stenting vs bypass for left main disease, new generation stents (BioFreedom, Orsiro, Absorb), transcatheter aortic valve implantation (Edwards Sapien XT, transcatheter embolic protection), and closure devices (Watchman, Amplatzer). New preventative cardiology data include trials of bariatric surgery, empagliflozin, liraglutide, semaglutide, PCSK9 inhibitors (evolocumab and alirocumab), and inclisiran. Antiplatelet therapy trials include platelet function monitoring and ticagrelor vs clopidogrel for peripheral vascular disease. New data are also presented in fields of heart failure (sacubitril/valsartan, aliskiren, spironolactone), atrial fibrillation (rivaroxaban in patients undergoing coronary intervention, edoxaban in DC cardioversion), cardiac devices (implantable cardioverter defibrillator in non-ischemic cardiomyopathy), and electrophysiology (cryoballoon vs radiofrequency ablation).

Conclusion

This paper presents a summary of key clinical cardiology trials during the past year and should be of practical value to both clinicians and cardiology researchers.



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In vivo effect of Commiphora swynnertonii ethanolic extracts on Trypanosoma congolense and selected immunological components in mice

The search for alternative trypanocidal compounds which can be available at affordable price is of paramount importance for control of trypanosomosis in human and animals. The current study evaluates the in vi...

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A multi-target therapeutic potential of Prunus domestica gum stabilized nanoparticles exhibited prospective anticancer, antibacterial, urease-inhibition, anti-inflammatory and analgesic properties.

Phytotherapeutics exhibit diverse pharmacological effects that are based on the combined action of a mixture of phytoconstituents. In this study, Prunus domestica gum-loaded, stabilized gold and silver nanopartic...

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EM Nerd-The Case of the Tardy Delegate

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We have discussed the dangers of surrogate outcomes at length, but none are more evident to an Emergency Physician than the time-based metrics we are subjected to on a daily basis. The latest of these temporal surrogates forced upon us is the 3-hour bundle of care in patients presenting to the Emergency Department with symptoms […]

EMCrit by Rory Spiegel.



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Biochemical markers in vascular cognitive impairment associated with subcortical small vessel disease - A consensus report

Vascular cognitive impairment (VCI) is a heterogeneous entity with multiple aetiologies, all linked to underlying vascular disease. Among these, VCI related to subcortical small vessel disease (SSVD) is emergi...

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Gene Expression Profiling in BRAF-Mutated Melanoma Reveals Patient Subgroups With Poor Outcomes to Vemurafenib That May Be Overcome by Cobimetinib Plus Vemurafenib

Purpose: The association of tumor gene expression profiles with progression-free survival (PFS) outcomes in patients with BRAFV600-mutated melanoma treated with vemurafenib or cobimetinib combined with vemurafenib was evaluated. <br /><br />Experimental Design: Gene expression of archival tumor samples from patients in four trials (BRIM-2, BRIM-3, BRIM-7, and coBRIM) was evaluated. Genes significantly associated with PFS (P<0 .05) were identified by univariate Cox proportional hazards modeling, then subjected to unsupervised hierarchical clustering, principal component analysis, and recursive partitioning to develop optimized gene signatures.<br /><br />Results: <p>Forty-six genes were identified as significantly associated with PFS in both BRIM-2 (n = 63) and the vemurafenib arm of BRIM-3 (n = 160). Two distinct signatures were identified: cell cycle and immune. Among vemurafenib-treated patients, the cell cycle signature was associated with shortened PFS compared with the immune signature in the BRIM-2/BRIM-3 training set (hazard ratio [HR] 1.8, 95% confidence interval [CI], 1.3-2.6, P = 0.0001) and in the coBRIM validation set (n = 101; HR 1.6, 95% CI, 1.0-2.5, P = 0.08). The adverse impact of the cell cycle signature on PFS was not observed in patients treated with cobimetinib combined with vemurafenib (n = 99; HR 1.1, 95% CI, 0.7-1.8, P = 0.66).</p> Conclusions: In vemurafenib-treated patients, the cell cycle gene signature was associated with shorter PFS. However, in cobimetinib combined with vemurafenib-treated patients, both cell cycle and immune signature subgroups had comparable PFS. Cobimetinib combined with vemurafenib may abrogate the adverse impact of the cell cycle signature.



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Shaping the tumor stroma and sparking immune activation by CD40 and 4-1BB signaling induced by an armed oncolytic virus

Purpose: Pancreatic cancer is a severe indication with short expected survival despite surgery and/or combination chemotherapeutics. Checkpoint blockade antibodies are approved for several cancer indications but pancreatic cancer has remained refractory. However, there are clinical data suggesting that stimulation of the CD40 pathway may be of interest for these patients. Oncolytic viruses armed with immunostimulatory genes represent an interesting approach. Herein we present LOAd703, a designed adenovirus armed with trimerized CD40L and 4-1BBL that activate the CD40 and 4-1BB pathways, respectively. Since many cells in the tumor stroma, including stellate cells, and the infiltrating immune cells express CD40 and some 4-1BB, we hypothesize that LOAd703 activates immunity and simultaneously modulates the biology of the tumor stroma. <p>Experimental design: Tumor-, stellate-, endothelial-, and immune cells were infected by LOAd703 and investigated by flow cytometry, proteomics and functional analyses.</p> <p>Results: LOAd703-infected pancreatic cell lines were killed by oncolysis and the virus was more effective than standard of care gemcitabine. In in vivo xenograft models, LOAd703 efficiently reduced established tumors and could be combined with gemcitabine for additional effect. Infected stellate- and tumor cells reduced factors that promote tumor growth (Spp-1, Gal-3, HGF, TGF-beta and collagen type I), while chemokines were increased. Molecules involved in lymphocyte migration were upregulated on infected endothelial cells. Dendritic cells were robustly stimulated by LOAd703 to produce co-stimulators, cytokines and chemokines, and such DCs potently expanded both antigen-specific T cells and NK cells. Conclusions: LOAd703 is a potent immune activator that modulates the stroma to support antitumor responses.



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Immune correlates of GM-CSF and melanoma peptide vaccination in a randomized trial for the adjuvant therapy of resected high-risk melanoma (E4697)

Purpose: E4697 was a multi-center intergroup randomized placebo-controlled Phase III trial of adjuvant GM-CSF and/or a multi-epitope melanoma peptide vaccine for patients with completely resected, high-risk stage III/IV melanoma. <p>Experimental Design: 815 patients were enrolled from 12/99 to 10/06 into this 6-arm study. GM-CSF was chosen to promote the numbers and functions of dendritic cells (DC). The melanoma antigen peptide vaccine (Tyrosinase368-376 (370D), gp100209-217 (210M), MART-127-35) in Montanide was designed to promote melanoma specific CD8+ T cell responses.</p> <p>Results: Although the overall RFS and OS were not significantly improved with the vaccine or GM-CSF when compared with placebo, immunomodulatory effects were observed in peripheral blood and served as important correlates to this therapeutic study. Peripheral blood was examined to evaluate the impact of GM-CSF and/or the peptide vaccine on peripheral blood immunity and to investigate potential predictive or prognostic biomarkers. 11.3% of unvaccinated patients and 27.1% of vaccinated patients developed peptide-specific CD8+ T cell responses. HLA-A2+ patients who had any peptide-specific CD8+ T cell response at day +43 tended to have poorer OS in univariate analysis. Patients receiving GM-CSF had significant reduction in percentages of circulating myeloid dendritic cells (mDC) and plasmacytoid DC (pDC) at day +43. In a subset of patients who received GM-CSF, circulating myeloid-derived suppressor cells (MDSC), and anti-GM-CSF neutralizing antibodies (Nabs) were also modulated. The majority of patients developed anti-GM-CSF Nabs, which correlated with improved RFS and OS.</p> Conclusions: The assessment of cellular and humoral responses identified counter-intuitive immune system changes correlating with clinical outcome.



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CHRONIC LYMPHOCYTIC LEUKEMIA WITH MUTATED IGHV4-34 RECEPTORS: SHARED AND DISTINCT IMMUNOGENETIC FEATURES AND CLINICAL OUTCOMES

Purpose:We sought to investigate if B cell receptor immunoglobulin (BcR IG) stereotypy is associated with particular clinicobiological features amongst chronic lymphocytic leukemia (CLL) patients expressing mutated BcR IG (M-CLL) encoded by the IGHV4-34 gene, and also ascertain whether these associations could refine prognostication.<br /> <p>Experimental Design: In a series of 19,907 CLL cases with available immunogenetic information, we identified 339 IGHV4-34 expressing cases assigned to one of the four largest stereotyped M-CLL subsets, namely subsets #4, #16, #29 and #201, and investigated in detail their clinicobiological characteristics and disease outcomes.</p> Results:We identified shared and subset-specific patterns of somatic hypermutation (SHM) amongst patients assigned to these subsets. The greatest similarity was observed between subsets #4 and #16, both including IgG-switched cases (IgG-CLL). In contrast, the least similarity was detected between subsets #16 and #201, the latter concerning IgM/D-expressing CLLs. Significant differences between subsets also involved disease stage at diagnosis and the presence of specific genomic aberrations. IgG subsets #4 and #16 emerged as particularly indolent with a significantly (p<0.05) longer time-to-first-treatment (TTFT) (median TTFT: not yet reached) compared to the IgM/D subsets #29 and #201 (median TTFT: 11 and 12 years, respectively).<br /><br />Conclusions:Our findings support the notion that BcR IG stereotypy further refines prognostication in CLL, superseding the immunogenetic distinction based solely on SHM load. Additionally, the observed distinct genetic aberration landscapes and clinical heterogeneity suggests that not all M-CLL cases are equal, prompting further research into the underlying biological background with the ultimate aim of tailored patient management.



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Development and validation of an ultra-deep next-generation sequencing assay for testing of plasma cell-free DNA from patients with advanced cancer

Purpose: Tumor-derived cell-free DNA (cfDNA) in plasma can be used for molecular testing and provide an attractive alternative to tumor tissue. Commonly used PCR-based technologies can test for limited number of alterations at the time. Therefore, novel ultrasensitive technologies capable of testing for a broad spectrum of molecular alterations are needed to further personalized cancer therapy. <p>Experimental Design: We developed a highly sensitive ultra-deep next-generation sequencing (NGS) assay using reagents from TruSeqNano library preparation and NexteraRapid Capture target enrichment kits to generate plasma cfDNA sequencing libraries for mutational analysis in 61 cancer-related genes using common bioinformatics tools. The results were retrospectively compared to molecular testing of archival primary or metastatic tumor tissue obtained at different points of clinical care.</p> <p>Results: In a study of 55 patients with advanced cancer, the ultra-deep NGS assay detected 82% (complete detection) to 87% (complete and partial detection) of the aberrations identified in discordantly collected corresponding archival tumor tissue. Patients with a low variant allele frequency (VAF) of mutant cfDNA survived longer than those with a high VAF did (P=0.018). In patients undergoing systemic therapy, radiological response was positively associated with changes in cfDNA VAF (P=0.02), and  compared with unchanged/increased mutant cfDNA VAF, decreased cfDNA VAF was associated with longer time to treatment failure (TTF; P=0.03).</p> <p>Conclusions: Ultra-deep NGS assay has good sensitivity compared to conventional clinical mutation testing of archival specimens. A high VAF in mutant cfDNA corresponded with shorter survival. Changes in VAF of mutated cfDNA were associated with TTF.



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Natural Language Processing and Fuzzy Tools for Business Processes in a Geolocation Context

In the geolocation field where high-level programs and low-level devices coexist, it is often difficult to find a friendly user interface to configure all the parameters. The challenge addressed in this paper is to propose intuitive and simple, thus natural language interfaces to interact with low-level devices. Such interfaces contain natural language processing (NLP) and fuzzy representations of words that facilitate the elicitation of business-level objectives in our context. A complete methodology is proposed, from the lexicon construction to a dialogue software agent including a fuzzy linguistic representation, based on synonymy.

http://ift.tt/2qUlnFS

Williams-Beuren Syndrome and Congenital Lobar Emphysema: Uncommon Association with Common Pathology?

Introduction. Congenital lobar emphysema (CLE) and Williams-Beuren Syndrome are two rare conditions that have only been reported together in a single case study. Case Presentation. We report another case of a male Caucasian newborn with nonspecific initial respiratory distress, with detection of CLE on repeat chest X-ray on Day 25 of life and concurrent ventricular septal defect, supravalvular aortic stenosis, and branch pulmonary stenosis, in whom a 7q11.23 deletion consistent with Williams-Beuren Syndrome was made. Conclusion. A diagnosis of congenital lobar emphysema should prompt further screening for congenital heart disease and genetic deletion, and further research is needed to investigate the role of elastin gene mutation in the development of the neonatal lung.

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Assessment of the Albumin-Bilirubin (ALBI) Grade as a Prognostic Indicator for Hepatocellular Carcinoma Patients Treated With Radioembolization.

Objective: As the utility of Child-Pugh (C-P) class is limited by the subjectivity of ascites and encephalopathy, we evaluated a previously established objective method, the albumin-bilirubin (ALBI) grade, as a prognosticator for yttrium-90 radioembolization (RE) treatment for patients with hepatocellular carcinoma (HCC). Materials and Methods: A total of 117 patients who received RE for HCC from 2 academic centers were reviewed and stratified by ALBI grade, C-P class, and Barcelona Clinic Liver Cancer stage. The overall survival (OS) according to these 3 criteria was evaluated by Kaplan-Meier survival analysis. The utilities of C-P class and ALBI grade as prognostic indicators were compared using the log-rank test. Multivariate Cox regression analysis was performed to identify additional predictive factors. Results: Patients with ALBI grade 1 (n=49) had superior OS than those with ALBI grade 2 (n=65) (P=0.01). Meanwhile, no significant difference was observed in OS between C-P class A (n=100) and C-P class B (n=14) (P=0.11). For C-P class A patients, the ALBI grade (1 vs. 2) was able to stratify 2 clear and nonoverlapping subgroups with differing OS curves (P=0.03). Multivariate Cox regression test identified alanine transaminase, Barcelona Clinic Liver Cancer stage, and ALBI grade as the strongest prognostic factors for OS (P

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Clinical, Biochemical, and Genetic Aspects of Sjögren-Larsson Syndrome

Abstract

Sjögren-Larsson syndrome (SLS) is caused by an autosomal recessive mutation in ALDH3A2, which encodes the fatty aldehyde dehydrogenase responsible for the metabolism of long-chain aliphatic aldehydes and alcohols. The pathophysiologic accumulation of aldehydes in various organs, including the skin, brain, and eyes, leads to characteristic features of ichthyosis, intellectual disability, spastic di-/quadriplegia, and low visual acuity with photophobia. The severity of the clinical manifestations thereof can vary greatly, although most patients are bound to a wheelchair due to contractures. To date, correlations between genotype and phenotype have proven difficult to document due to low disease incidence and high heterogenetic variability in mutations. This review summarizes the clinical characteristics of SLS that have been found to contribute to the prognosis thereof, as well as recent updates from genetic and brain imaging studies. Additionally, the differential diagnoses of SLS are briefly illustrated, covering cerebral palsy and other genetic or neurocutaneous syndromes mimicking the syndrome.

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Pathogenic variations of ALDH3A2 encoding fatty aldehyde dehydrogenase (FALDH) cause Sjögren-Larsson syndrome



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Disruption of YWHAE gene at 17p13.3 causes learning disabilities and brain abnormalities.

Abstract

There is a broad phenotypic spectrum of patients with 17p13.3 deletions. One of the most prominent features is lissencephaly caused by haploinsufficiency of the gene PAFAH1B1. The deletion of this gene and those distal to it, results in Miller-Dieker syndrome, however there have been many reports of patients with haploinsufficiency of the distal genes alone. The deletions of these genes including YWHAE, CRK and TUSC5 have been studied extensively and YWHAE has been postulated to be the cause of neurological abnormalities. The patients with deletions of the Miller-Dieker syndrome distal region present with variable clinical features including brain abnormalities, growth retardation, developmental delay, facial dysmorphisms and seizures. While there have been many patients reported to have deletions involving the YWHAE gene along with other genes, here we present the first detailed clinical description of a patient with deletion of YWHAE alone, allowing a more accurate characterization of the pathogenicity of YWHAE haploinsufficiency. The patient reported here demonstrated brain abnormalities, learning disabilities, and seizures supporting the role of YWHAE in these features. We review the literature and use this case report to better characterize and further confirm the genotype phenotype relationship of the genes within the critical region of Miller-Dieker Syndrome.

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On the complexity of clinical and molecular bases of neurodegeneration with brain iron accumulation

ABSTRACT

Neurodegeneration with brain iron accumulation (NBIA) are a group of inherited heterogeneous neurodegenerative rare disorders. These patients present with dystonia, spasticity, parkinsonism and neuropsychiatric disturbances, along with brain MRI evidence of iron accumulation. In sum, they are devastating disorders and to date, there is no specific treatment. Ten NBIA genes are accepted: PANK2, PLA2G6, C19orf12, COASY, FA2H, ATP13A2, WDR45, FTL, CP, and DCAF17, and. Nonetheless, a relevant percentage of patients remain without genetic diagnosis, suggesting that other novel NBIA genes remain to be discovered. Overlapping complex clinical pictures render an accurate differential diagnosis difficult. Little is known about the pathophysiology of NBIAs. The reported NBIA genes take part in a variety of pathways: CoA synthesis, lipid and iron metabolism, autophagy, and membrane remodeling. The next generation sequencing revolution has achieved relevant advances in genetics of Mendelian diseases and will provide new genes for NBIAs, which will be investigated according to two main strategies: genes involved in disorders with similar phenotype and genes that play a role in a pathway of interest. To achieve an effective therapy for NBIA patients, a better understanding of the biological process underlying disease is crucial, moving towards a new age of precision medicine.

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Effect of Amplatz Sheath on Cystolithotripsy for Women with Large Bladder Stone

Objective. This study compared the effect of endourological procedures with or without the Amplatz sheath (AS) on cystolithotripsy. Methods. We retrospectively analysed 18 patients who underwent treatment for bladder stone over 30 mm. This study consisted of two groups, namely, patients who underwent cystolithotripsy with an AS (AS group) and those who underwent standard procedure without an AS (SP group). The stone-free rate, total energy used for operation, operation time, days of admission after operation, and complication of both groups were compared. Results. The number of patients in the AS and SP groups was 10 and 8, respectively. Significant differences were not found between these two groups with regard to age, stone burden, stone volume, number of stones, and history of neurogenic bladder. All patients in both groups achieved a stone-free state. Total energy was significantly increased and operation time was shorter in the AS group. No significant difference was observed in terms of days of admission after operation. Any complications were not increased by the use of AS. Struvite was the most common stone component in both groups. Conclusion. Use of an AS can shorten the operation time of cystolithotripsy without increasing perioperative complication.

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Txndc9 Is Required for Meiotic Maturation of Mouse Oocytes

Txndc9 (thioredoxin domain containing protein 9) has been shown to be involved in mammalian mitosis; however, its function in mammalian oocyte meiosis remains unclear. In this study, we initially found that Txndc9 is expressed during meiotic maturation of mouse oocytes and higher expression of Txndc9 mRNA and protein occurred in germinal vesicle (GV) stage. By using confocal scanning, we observed that Txndc9 localized at both nucleus and cytoplasm, especially at spindle microtubules. Specific depletion of Txndc9 by siRNA in mouse oocyte resulted in decreasing the rate of first polar body extrusion and increasing abnormal spindle assemble. Moreover, knockdown of Txndc9 in germinal vesicle (GV) stage oocytes led to higher level of reactive oxygen species (ROS) and lower level of antioxidant glutathione (GSH) as compared with control oocytes, which indicated that Txndc9 may be involved in mediating the redox balance. In summary, our results demonstrated that Txndc9 is crucial for mouse oocyte maturation by regulating spindle assembly, polar body extrusion, and redox status.

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Serum Metabolomics Profiling to Identify Biomarkers for Unstable Angina

Although statistical evidence is clear regarding the dangerousness of unstable angina (UA), a form of coronary heart disease (CHD) characterised by high mortality and morbidity globally, it is important to recognise that diagnostic precision for the condition is unfavourable. In the present research, to gain insight into candidate biomarkers, the author draws on 1H NMR-based serum metabolic profiling to analyze the unstable angina pectoris (UAP) metabolic signatures; this constitutes an effective way to produce medical diagnosis. 101 unstable angina pectoris patients and 132 healthy controls were enrolled and 22 serum samples from each group were analyzed. Effective separation was noted regarding the UAP and control groups, and, for the former group considered in relation to their counterpart, the serum concentrations of Lac, m-I, lipid, VLDL, 3-HB, and LDL were higher whereas the concentrations of Thr, Cr, Cho, PC/GPC, Glu, Gln, Lys, HDL, Ile, Leu, and Val were lower. The conclusion drawn in view of the results is that the plasma metabolomics examined by 1H NMR displayed promise for biomarker identification for UA. In addition to this, the analysis illuminated the metabolic processes of UA.

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Optimization of diagnostic performance for differentiation of recurrence from radiation necrosis in patients with metastatic brain tumors using tumor volume-corrected 11 C-methionine uptake

Abstract

Background

Tumor to normal tissue ratio (T/N ratio) on 11C-methionine (11C-MET) positron emission tomography/computed tomography (PET/CT) is affected by variable factors. We investigated whether T/N ratio cutoff values corrected according to metabolic tumor volume (MTV) could improve the diagnostic performance of 11C-MET PET/CT for diagnosis of recurrence in patients with metastatic brain tumor.

Forty-eight patients with metastatic brain tumors underwent 11C-MET PET/CT for differential diagnosis between recurrence and radiation necrosis after gamma knife radiosurgery (GKR). Both T/N ratio and MTV were estimated in each lesion on 11C-MET PET/CT. The lesions were classified into three groups based on MTV criteria (≤ 0.5 cm3; > 0.5, ≤ 4.0 cm3; and > 4.0 cm3). The optimal cutoff values of the T/N ratio from receiver operating characteristic (ROC) curve were determined in each group (MTV-corrected) as well as total lesions (non-corrected). Finally, diagnostic performance of 11C-MET PET/CT was compared with the MTV-corrected cutoff values.

Results

Among 77 lesions, 51 were diagnosed with recurrence. The mean T/N ratio was 2.25 (± 1.12) for recurrent lesions and 1.44 (± 0.22) for radiation necrosis (P < 0.001). T/N ratio of 1.61 (non-corrected) provided the best sensitivity, specificity, and diagnostic accuracy (70.6, 80.8, and 74.0%, respectively). Using the MTV criteria, optimal cutoff values of the T/N ratios in each group were 1.23 (MTV ≤ 0.5 cm3), 1.54 (0.5 cm3 < MTV ≤ 4.0 cm3), and 1.85 (MTV > 4.0 cm3). In small-sized lesions (MTV ≤ 0.5 cm3), MTV-corrected cutoff values (1.23) could maintain favorable diagnostic performance with sensitivity, specificity, and diagnostic accuracy (70.0, 80.0, and 73.3%, respectively), compared to non-corrected cutoff values.

Conclusions

MTV-corrected cutoff values of T/N ratio could maintain the diagnostic performance of 11C-MET PET/CT in small sized, metastatic brain tumors. We expect our results to contribute to reproducible and standardized interpretation of 11C-MET PET/CT.



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Clinical and imaging-based prognostic factors in radioembolisation of liver metastases from colorectal cancer: a retrospective exploratory analysis

Abstract

Background

The aim of this study was to investigate the relationship between absorbed dose and response of colorectal cancer liver metastases treated with [90Y]-resin microspheres and to explore possible clinical and imaging derived prognostic factors.

Methods

FDG PET/CT was used to measure response of individual lesions to a measured absorbed dose, derived from post-treatment 90Y PET imaging. Predicted dose was also derived from planning [99mTc]-MAA SPECT data. Peak standardised uptake value and total lesion glycolysis (TLG) were explored as response measures, and compared to dose metrics including average dose (D avg), biologically effective dose, minimum dose to 70% of lesion volume and volume receiving at least 50 Gy. Prognostic factors examined included baseline TLG, RAS mutation status, FDG heterogeneity and dose heterogeneity. In an exploratory analysis, response and clinico-pathological variables were evaluated and compared to overall survival.

Results

Sixty-three lesions were analysed from 22 patients. Poor agreement was seen between predicted and measured dose values. TLG was a superior measure of response, and all dose metrics were significant prognostic factors, with a D avg of ~50 Gy derived as the critical threshold for a significant response (>50% reduction in TLG). No significant correlation was found between baseline TLG or RAS mutation status and response. Measured dose heterogeneity was a significant prognostic factor and when combined with D avg had a positive predictive value for response >80%. In the exploratory analysis for prognostic factors of survival, low hepatic tumour burden and mean reduction in TLG >65% were independently associated with improved overall survival.

Conclusions

Lesions receiving an average dose greater than 50 Gy are likely to have a significant response. For lesions receiving less than 50 Gy, dose heterogeneity is a significant prognostic factor. Lesions receiving an average dose less than 20 Gy are unlikely to respond. A reduction in TLG may be associated with improved overall survival.



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Brigatinib Approved, but Treatment Role Uncertain [News in Brief]

Approval leaves questions about most effective sequence of drugs in non-small cell lung cancer.



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Gefitinib Delays NSCLC Recurrence After Surgery [News in Brief]

Patients who received the drug were disease-free 10 months longer than those given chemotherapy, study finds.



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Dynamic configuration management of a multi-standard and multi-mode reconfigurable multi-ASIP architecture for turbo decoding

The multiplication of connected devices goes along with a large variety of applications and traffic types needing diverse requirements. Accompanying this connectivity evolution, the last years have seen consid...

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Distinct roles of Hes1 in normal stem cells and tumor stem-like cells of the intestine

Cancer stem cells (CSC) have attracted attention as therapeutic targets, however, CSC-targeting therapy may disrupt normal tissue homeostasis because many CSC molecules are also expressed by normal stem cells (NSC). Here we demonstrate that NSC-specific and CSC-specific roles of the stem cell transcription factor Hes1 in the intestine enable the feasibility of a specific cancer therapy. Hes1 expression was upregulated in NSC and intestinal tumors. Lineage tracing experiments in adult mouse intestine revealed that Hes1 deletion in Lgr5+ or Bmi1+ NSC resulted in loss of self-renewal but did not perturb homeostasis. Further, in Lgr5+ NSC deletion of Hes1 stabilized β-catenin, limited tumor formation and prolonged host survival. Notably, in Lgr5+ or Dclk1+ tumor stem cells derived from established intestinal tumors, Hes1 deletion triggered immediate apoptosis, reducing tumor burden. Our results show how Hes1 plays different roles in NSC and CSC, in which Hes1 disruption leads to tumor regression without perturbing normal stem cell homeostasis, preclinically validating Hes1 as a cancer therapeutic target.

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Liver metastasis is facilitated by the adherence of circulating tumor cells to vascular fibronectin deposits

The interaction between circulating tumor cells (CTC) and endothelial cells during extravasation is a critical process during metastatic colonization, but its mechanisms remain poorly characterized. Here we report that the luminal side of liver blood vessels contains fibronectin deposits that are enriched in mice bearing primary tumors and are also present in vessels from human livers affected with metastases. Cancer cells attached to endothelial fibronectin deposits via talin1, a major component of focal adhesions. Talin1 depletion impaired cancer cell adhesion to the endothelium and transendothelial migration, resulting in reduced liver metastasis formation in vivo. Talin1 expression levels in patient CTC's correlated with prognosis and therapy response. Together, our findings uncover a new mechanism for liver metastasis formation involving an active contribution of hepatic vascular fibronectin and talin1 in cancer cells.

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The damaging effect of passenger mutations on cancer progression

Genomic instability and high mutation rates cause cancer to acquire numerous mutations and chromosomal alterations during its somatic evolution, most are termed passengers because they do not confer cancer phenotypes. Evolutionary simulations and cancer genomic studies suggest that mildly deleterious passengers accumulate and can collectively slow cancer progression. Clinical data also suggest an association between passenger load and response to therapeutics, yet no causal link between the effects of passengers and cancer progression has been established. To assess this, we introduced increasing passenger loads into human cell lines and immunocompromised mouse models. We found that passengers dramatically reduced proliferative fitness (~3% per Mb), slowed tumor growth, and reduced metastatic progression. We developed new genomic measures of damaging passenger load that can accurately predicted the fitness costs of passengers in cell lines and in human breast cancers. We conclude that genomic instability and elevated load of DNA alterations in cancer is a double-edged sword: it accelerates the accumulation of adaptive drivers, but incurs a harmful passenger load that can outweigh driver benefit. The effects of passenger alterations on cancer fitness were unrelated to enhanced immunity, as our tests were performed either in cell culture or in immunocompromised animals. Our findings refute traditional paradigms of passengers as neutral events, suggesting that passenger load reduces the fitness of cancer cells and slows or prevents progression of both primary and metastatic disease. The anti-tumor effects of chemotherapies can in part be due to induction of genomic instability and increased passenger load.

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Persistent immune stimulation exacerbates genetically-driven myeloproliferative disorders via stromal remodeling

Systemic immune stimulation has been associated with increased risk of myeloid malignancies, but the pathogenic link is unknown. We demonstrate in animal models that experimental systemic immune activation alters the bone marrow stromal microenvironment, disarranging extracellular matrix (ECM) microarchitecture, with down-regulation of SPARC and collagen-I and induction of complement activation. These changes were accompanied by a decrease in Treg frequency and by an increase in activated effector T cells. Under these conditions, hematopoietic precursors harboring nucleophosmin-1 (NPM1) mutation generated myeloid cells unfit for normal hematopoiesis but prone to immunogenic death, leading to neutrophil extracellular trap (NET) formation. NET fostered the progression of the indolent NPM1-driven myeloproliferation toward an exacerbated and proliferative dysplastic phenotype. Enrichment in NET structures was found in the bone marrow of patients with autoimmune disorders and in NPM1-mutated AML patients. Genes involved in NET formation in the animal model were used to design a NET-related inflammatory gene signature for human myeloid malignancies. This signature identified two AML subsets with different genetic complexity and different enrichment in NPM1 mutation and predicted the response to immunomodulatory drugs. Our results indicate that stromal/ECM changes and priming of bone marrow NETosis by systemic inflammatory conditions can complement genetic and epigenetic events towards the development and progression of myeloid malignancy.

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Immune checkpoint blockade, immunogenic chemotherapy or IFN-{alpha} blockade boost the local and abscopal effects of oncolytic virotherapy

Athough the clinical efficacy of oncolytic viruses has been demonstrated for local treatment, the ability to induce immune-mediated regression of distant metastases is still poorly documented. We report here that the engineered oncolytic vaccinia virus VVWR-TK-RR--Fcu1 can induce immunogenic cell death and generate a systemic immune response. Effects on tumor growth and survival was largely driven by CD8+ T cells, and immune cell infiltrate in the tumor could be reprogrammed towards a higher ratio of effector T cells to regulatory CD4+ T cells. The key role of type 1-IFN pathway in oncolytic virotherapy was also highlighted, as we observed a strong abscopal response in Ifnar-/- tumors. In this model, single administration of virus directly into the tumors one one flank led to regression in the contralateral flank. Moreover, these effects were further enhanced when oncolytic treatment was combined with immunogenic chemotherapy or with immune checkpoint blockade. Taken together, our results suggest how to safely improve the efficacy of local oncolytic virotherapy in patients whose tumors are characterized by dysregulated IFN-α signaling.

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3D mathematical modeling of glioblastoma suggests that transdifferentiated vascular endothelial cells mediate resistance to current standard-of-care therapy

Glioblastoma (GBM), the most aggressive brain tumor in human patients, is decidedly heterogeneous and highly vascularized. Glioma stem/initiating cells (GSC) are found to play a crucial role by increasing cancer aggressiveness and promoting resistance to therapy. Recently, crosstalk between GSC and vascular endothelial cells has been shown to significantly promote GSC self-renewal and tumor progression. Further, GSC also transdifferentiate into bona-fide vascular endothelial cells (GEC), which inherit mutations present in GSC and are resistant to traditional anti-angiogenic therapies. Here we use 3D mathematical modeling to investigate GBM progression and response to therapy. The model predicted that GSC drive invasive fingering and that GEC spontaneously form a network within the hypoxic core, consistent with published experimental findings. Standard-of-care treatments using DNA-targeted therapy (radiation/chemo) together with anti-angiogenic therapies, reduced GBM tumor size but increased invasiveness. Anti-GEC treatments blocked the GEC support of GSC and reduced tumor size but led to increased invasiveness. Anti-GSC therapies that promote differentiation or disturb the stem cell niche effectively reduced tumor invasiveness and size, but were ultimately limited in reducing tumor size because GEC maintain GSC. Our study suggests that a combinatorial regimen targeting the vasculature, GSC, and GEC, using drugs already approved by the FDA, can reduce both tumor size and invasiveness and could lead to tumor eradication.

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SIRT3-mediated dimerization of IDH2 directs cancer cell metabolism and tumor growth

The isocitrate dehydrogenase IDH2 produces α-ketoglutarate by oxidizing isocitrate, linking glucose metabolism to oxidative phosphorylation. In this study, we report that loss of SIRT3 increases acetylation of IDH2 at lysine 413 (IDH2-K413-Ac), thereby decreasing its enzymatic activity by reducing IDH2 dimer formation. Expressing a genetic acetylation mimetic IDH2 mutant (IDH2K413Q) in cancer cells decreased IDH2 dimerization and enzymatic activity and increased cellular reactive oxygen species (ROS) and glycolysis, suggesting a shift in mitochondrial metabolism. Concurrently, overexpression of IDH2K413Q promoted cell transformation and tumorigenesis in nude mice, resulting in a tumor-permissive phenotype. Immunohistochemical staining showed that IDH2 acetylation was elevated in high-risk luminal B patients relative to low-risk luminal A patients. Overall, these results suggest a potential relationship between SIRT3 enzymatic activity, IDH2-K413 acetylation-determined dimerization, and a cancer-permissive phenotype.

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Erratum to: Abstracts from the 8th International Congress of the Asia Pacific Society of Infection Control (APSIC)



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Anal cancer: French Intergroup Clinical Practice Guidelines for diagnosis, treatment and follow-up

This document is a summary of the French Intergroup guidelines regarding the management of anal carcinomas, published in November 2016.

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Ductal Stones Recurrence After Extracorporeal Shock Wave Lithotripsy For Difficult Common Bile Duct Stones: Predictive Factors

Extra-corporeal shock wave lithotripsy (ESWL) can be considered in difficult common bile duct stones (DCBDS), with a success rate greater than 90% but data on stone recurrence after ESWL are limited. We performed a retrospective analysis to evaluate long-term outcomes in patients who underwent ESWL for DCBDS.

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TGR5 contributes to hepatic cystogenesis in rodents with polycystic liver diseases via cAMP/Gαs signaling

Abstract

Hepatic cystogenesis in Polycystic Liver Disease (PLD) is associated with increased levels of cAMP in cholangiocytes lining liver cysts. TGR5, a G protein-coupled bile acid receptor, is linked to cAMP and expressed in cholangiocytes. Therefore, we hypothesized that TGR5 might contribute to disease progression. We examined expression of TGR5 and Gα proteins in cultured cholangiocytes and in livers of animal models and humans with PLD. In vitro, we assessed cholangiocyte proliferation, cAMP levels, and cyst growth in response to: (i) TGR5 agonists [taurolithocholic acid (TLCA), oleanolic acid (OA) and two synthetic compounds]; (ii) a novel TGR5 antagonist (SBI-115); and (iii) a combination of SBI-115 and pasireotide, a somatostatin receptor (SSTR) analog. In vivo, we examined hepatic cystogenesis in OA-treated PCK rats and after genetic elimination of TGR5 in double mutant TGR5-/-;Pkhd1del2/del2 mice. Compared to control, expression of TGR5 and Gαs (but not Gαi and Gαq) proteins was increased 2-3-fold in cystic cholangiocytes in vitro and in vivo. In vitro, TGR5 stimulation enhanced cAMP production, cell proliferation and cyst growth by ∼40%; these effects were abolished after TGR5 reduction by shRNA. OA increased cystogenesis in PCK rats by 35%; in contrast, hepatic cystic areas were decreased by 45% in TGR5-deficient TGR5-/-;Pkhd1del2/del2 mice. TGR5 expression and its co-localization with Gαs were increased ∼2-fold upon OA treatment. Levels of cAMP, cell proliferation and cyst growth in vitro were decreased by ∼30% in cystic cholangiocytes after treatment with SBI-115 alone and by ∼50% when SBI-115 was combined with pasireotide. Conclusion: TGR5 contributes to hepatic cystogenesis by increasing cAMP and enhancing cholangiocyte proliferation. Our data suggest that a TGR5 antagonist alone or concurrently with SSTR agonists represents novel therapeutic approaches in PLD. This article is protected by copyright. All rights reserved.



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Death and Liver Transplantation within Two Years of Onset of Drug-Induced Liver Injury

Abstract

Drug-induced liver injury (DILI) is an important cause of death and indication for liver transplantation (fatality). The role of DILI in these fatalities ispoorly characterized particularly when fatalities occur > 26 weeks after DILI onset. We analyzed patients in the U.S. Drug-Induced Liver Injury Network prospective study having a fatal outcome within 2 years of onset. Each case was reviewed by 8 Network investigators and categorized as DILI having a primary, contributory or no role in the fatality. We subcategorized primary role cases as acute, chronic, acute-on-chronic or acute cholestatic liver failure. For contributory and no role cases, we assigned a primary cause of death. Among 1089 patients, 107 (9.8%) fatalities occurred within 2 years. DILI had a primary role in 68 (64%), a contributory role in 15 (14%) and no role in 22 (21%); 2 had insufficient data. Among primary role cases, 74% had acute, 13% chronic, 7% acute-on-chronic and 6% acute cholestatic failure. For the 15 contributory role cases, common causes of death included sepsis, malignancy and severe cutaneous reactions with multi-organ failure. For the 22 no role cases, malignancies accounted for most fatalities. Higher bilirubin, coagulopathy, leukocytosis and thrombocytopenia were independently associated with DILI fatalities. nR Hy's Law had a higher positive predictive value for overall fatality (14% vs. 10%) and stronger independent association with DILI fatalities within 26 weeks compared to the original version of Hy's Law (HR: 6.2, CI 3.4 – 11.1 vs. 2.2, CI 1.3-3.7). DILI leads directly or indirectly to fatality in 7.6% of cases; 40% of these have non-acute liver failure courses. nR Hy's Law better identifies risk for death compared to the original Hy's Law. This article is protected by copyright. All rights reserved.



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Randomised clinical trial: mesalazine versus placebo in the prevention of diverticulitis recurrence

Summary

Background

Previous studies have reached conflicting conclusions regarding the efficacy of mesalazine in the prevention of recurrent diverticulitis.

Aim

To investigate the efficacy and safety of mesalazine granules in the prevention of recurrence of diverticulitis after acute uncomplicated diverticulitis.

Methods

Two phase 3, randomised, placebo-controlled, double-blind multicentre trials (SAG-37 and SAG-51) investigated mesalazine granules in patients with prior episodes (<6 months) of uncomplicated left-sided diverticulitis. Patients were randomised to receive either 3 g mesalazine once daily or placebo (SAG-37, n=345) or to receive either 1.5 g mesalazine once daily, 3 g once daily or placebo for 96 weeks (SAG-51, n=330). The primary endpoint was the proportion of recurrence-free patients during 48 weeks (SAG-37 and SAG-51) or 96 weeks (SAG-51) of treatment.

Results

Mesalazine did not increase the proportion of recurrence-free patients over 48 or 96 weeks compared to placebo. In SAG-37, the proportion of recurrence-free patients during 48 weeks was 67.9% with mesalazine and 74.4% with placebo (P=.226). In SAG-51, the proportion of recurrence-free patients over 48 weeks was 46.0% with 1.5 g mesalazine, 52.0% with 3 g mesalazine and 58.0% with placebo (P=.860 for 3 g mesalazine vs placebo) and over 96 weeks 6.9%, 9.8% and 23.1% respectively (P=.980 for 3 g mesalazine vs placebo). Patients with only one diverticulitis episode in the year prior to study entry had a lower recurrence risk compared to >1 episode. Safety data revealed no new adverse events.

Conclusion

Mesalazine was not superior to placebo in preventing recurrence of diverticulitis.



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The use of selective serotonin receptor inhibitors (SSRIs) is not associated with increased risk of endoscopy-refractory bleeding, rebleeding or mortality in peptic ulcer bleeding

Summary

Background

Observational studies have consistently shown an increased risk of upper gastrointestinal bleeding in users of selective serotonin receptor inhibitors (SSRIs), probably explained by their inhibition of platelet aggregation. Therefore, treatment with SSRIs is often temporarily withheld in patients with peptic ulcer bleeding. However, abrupt discontinuation of SSRIs is associated with development of withdrawal symptoms in one-third of patients. Further data are needed to clarify whether treatment with SSRIs is associated with poor outcomes, which would support temporary discontinuation of treatment.

Aim

To identify if treatment with SSRIs is associated with increased risk of: (1) endoscopy-refractory bleeding, (2) rebleeding or (3) 30-day mortality due to peptic ulcer bleeding.

Methods

A nationwide cohort study. Analyses were performed on prospectively collected data on consecutive patients admitted to hospital with peptic ulcer bleeding in Denmark in the period 2006-2014. Logistic regression analyses were used to investigate the association between treatment with SSRIs and outcome following adjustment for pre-defined confounders. Sensitivity and subgroup analyses were performed to evaluate the validity of the findings.

Results

A total of 14 343 patients were included. Following adjustment, treatment with SSRIs was not associated with increased risk of endoscopy-refractory bleeding (odds ratio [OR] [95% Confidence Interval (CI)]: 1.03 [0.79-1.33]), rebleeding (OR [95% CI]: 0.96 [0.83-1.11]) or 30-day mortality (OR [95% CI]: 1.01 [0.85-1.19]. These findings were supported by sensitivity and subgroup analyses.

Conclusions

According to our data, treatment with SSRIs does not influence the risk of endoscopy-refractory bleeding, rebleeding or 30-day mortality in peptic ulcer bleeding.



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HeartMate II LVAS Pocket System Controller by Abbott-Thoratec: Class I Recall - Due to Risk of Patient Injury and/or Death during Backup Controller Exchange

[Posted 05/23/2017] AUDIENCE: Cardiology, Risk Manager, Nursing, Patient ISSUE: Abbott-Thoratec has received a total of 70 reports of incidents in which the controller has malfunctioned after an exchange, including 19 injuries and 26 deaths. All of...

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Fluid responsiveness predicted by transcutaneous partial pressure of oxygen in patients with circulatory failure: a prospective study

Significant effort has been devoted to defining parameters for predicting fluid responsiveness. Our goal was to study the feasibility of predicting fluid responsiveness by transcutaneous partial pressure of ox...

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HeartMate II LVAS Pocket System Controller by Abbott-Thoratec: Class I Recall - Due to Risk of Patient Injury and/or Death during Backup Controller Exchange

[Posted 05/23/2017] AUDIENCE: Cardiology, Risk Manager, Nursing, Patient ISSUE: Abbott-Thoratec has received a total of 70 reports of incidents in which the controller has malfunctioned after an exchange, including 19 injuries and 26 deaths. All of...

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Effects of Adjuvant Radiotherapy in Patients With Synovial Sarcoma

imageObjectives: To analyze the treatment outcomes and the effects of adjuvant radiotherapy (RT) in patients with synovial sarcoma (SS). Materials and Methods: The medical records of 103 patients treated with definitive surgery for SS, with/without RT, from August 1982 to July 2013 were reviewed retrospectively. The median age of the patients was 33 years (range, 5 to 72 y). The most frequent tumor location was the extremities (79 patients, 77%). Seventy-five patients (73%) received adjuvant RT and 26 (25%) did not. The median dose of adjuvant RT was 61.2 Gy (range, 45 to 66.6 Gy). Results: The median follow-up period was 5.4 years (range, 0.2 to 31.0 y). The 5- and 10-year overall survival rates were 77 % and 65%, respectively. The progression-free survival (PFS) rates at 5 and 10 years were 52% and 43%, respectively. The most common site of initial failure was the lung (24 patients), followed by local recurrence (14 patients). The 5-year local-recurrence-free survival (LRFS) and distant-metastasis-free survival (DMFS) rates were 80% and 63%, respectively. On multivariate analysis, a mitosis count of

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Use of Metabolic Parameters as Prognostic Factors During Concomitant Chemoradiotherapy for Locally Advanced Cervical Cancer

imageObjectives: To investigate the use of metabolic parameters as early prognostic factors during concomitant chemoradiotherapy for locally advanced cervix carcinoma (LACC). Materials and Methods: Between February 2008 and January 2012, 34 consecutive patients treated for LACC (International Federation of Gynecology and Obstetrics Staging System stage IB2-IVA) were included in a retrospective study. Treatment was standard of care: total dose of 45 Gy in 1.8 Gy per fraction with concurrent cisplatin followed by brachytherapy. 18F-FDG PET-CT modalities were performed before treatment and per-treatment (at 40 Gy). The analyzed parameters were: maximum standardized uptake value (SUVmax), SUVmax variations of the primary tumor between the 2 investigations (DSUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG). Survival was assessed according to early metabolic changes during chemoradiotherapy. Results: Median follow-up was 16 months (range, 5.3 to 32.4 mo). Median SUVmax before treatment was 13.15 (5.9 to 31) and was 5.05 (0 to 12) per-treatment. Median DSUVmax was 63.97% (0% to 100%). Median MTV before treatment was 44.16 mL (3.392 to 252.768 mL) and was 5.44 mL (0 to 69.88 mL) per-treatment. Median TLG before treatment was 249.82 mL (13.40 to 1931.10 mL) and was 20.14 mL (0 to 349.99 mL) per-treatment. At 40 Gy, SUVmax≥6, DSUVmax≤40%, MTV≥5.6 mL, and TLG≥21.6 mL were significantly associated with overall survival and progression-free survival reduction. MTV predicted progression with a sensitivity of 80% and a specificity of 87.5% and TLG with a sensitivity of 80% and a specificity of 83.3%. Conclusions: PET-CT imaging could be useful as an early prognostic factor during treatment for LACC. MTV and TLG seem to provide better prognostic information than SUVmax and DSUVmax.

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CNS Hemangiopericytoma: A Systematic Review of 523 Patients

imageBackground: Central nervous system (CNS) hemangiopericytomas are rare mesenchymal tumors of the brain. In the absence of randomized clinical trials or large studies, the only information we have about the natural history and the management is from isolated clinical case series. They have suggested that surgery is beneficial, with conflicting results on the role of complete resection and adjuvant radiation. We have conducted a systematic review of clinical case series of CNS hemangiopericytoma analyzing the biology of the tumor and the best follow-up and management strategy. Methods: Fifteen pertinent clinical case series on newly diagnosed CNS hemangiopericytoma were selected by a review of literature. A total of 523 patients were analyzed for age, sex, mode of recurrence and metastases, and survival after complete/incomplete resection with or without radiation. Results: The mean age was found to be 44.17 (±3.59) years. The incidence was higher in male individuals younger than 45 years and in older female individuals. Complete resection and adjuvant radiation significantly improved survival in comparison with incomplete resection and no radiation, respectively (P

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Complete Neoadjuvant Treatment for Rectal Cancer: The Brown University Oncology Group CONTRE Study

imagePurpose: Following preoperative chemoradiation and surgery, many patients with stage II to III rectal cancer are unable to tolerate full-dose adjuvant chemotherapy. BrUOG R-224 was designed to assess the impact of COmplete Neoadjuvant Treatment for REctal cancer (CONTRE), primary chemotherapy followed by chemoradiation and surgery, on treatment delivery, toxicities, and pathologic response at surgery. Methods: Patients with clinical stage II to III (T3 to T4 and/or N1 to N2) rectal cancer received 8 cycles of modified FOLFOX6 followed by capecitabine 825 mg/m2 bid concurrent with 50.4 Gy intensity-modulated radiation therapy. Surgery was performed 6 to 10 weeks after chemoradiation. Results: Thirty-nine patients were enrolled between August 2010 and June 2013. Median age was 61 years (30 to 79 y); 7 patients (18%) were clinical stage II and 32 (82%) stage III. Thirty-six patients (92%) received all 8 cycles of mFOLFOX6, of whom 35 completed subsequent chemoradiation; thus 89% of patients received CONTRE as planned. No unexpected toxicities were reported. All patients had resolution of bleeding and improvement of obstructive symptoms, with no complications requiring surgical intervention. Pathologic complete response (ypT0N0) was demonstrated in 13 patients (33%; 95% CI, 18.24%-47.76%). Conclusions: CONTRE seems to be a well-tolerated alternative to the current standard treatment sequence. Evaluating its impact on long-term outcomes would require a large randomized trial, but using pathologic response as an endpoint, it could serve as a platform for assessing the addition of novel agents to preoperative treatment in stage II to III rectal cancer.

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Longitudinal DSC-MRI for Distinguishing Tumor Recurrence From Pseudoprogression in Patients With a High-grade Glioma

imageObjective: For patients with high-grade glioma on clinical trials it is important to accurately assess time of disease progression. However, differentiation between pseudoprogression (PsP) and progressive disease (PD) is unreliable with standard magnetic resonance imaging (MRI) techniques. Dynamic susceptibility contrast perfusion MRI (DSC-MRI) can measure relative cerebral blood volume (rCBV) and may help distinguish PsP from PD. Methods: A subset of patients with high-grade glioma on a phase II clinical trial with temozolomide, paclitaxel poliglumex, and concurrent radiation were assessed. Nine patients (3 grade III, 6 grade IV), with a total of 19 enhancing lesions demonstrating progressive enhancement (≥25% increase from nadir) on postchemoradiation conventional contrast-enhanced MRI, had serial DSC-MRI. Mean leakage-corrected rCBV within enhancing lesions was computed for all postchemoradiation time points. Results: Of the 19 progressively enhancing lesions, 10 were classified as PsP and 9 as PD by biopsy/surgery or serial enhancement patterns during interval follow-up MRI. Mean rCBV at initial progressive enhancement did not differ significantly between PsP and PD (2.35 vs. 2.17; P=0.67). However, change in rCBV at first subsequent follow-up (−0.84 vs. 0.84; P=0.001) and the overall linear trend in rCBV after initial progressive enhancement (negative vs. positive slope; P=0.04) differed significantly between PsP and PD. Conclusions: Longitudinal trends in rCBV may be more useful than absolute rCBV in distinguishing PsP from PD in chemoradiation-treated high-grade gliomas with DSC-MRI. Further studies of DSC-MRI in high-grade glioma as a potential technique for distinguishing PsP from PD are indicated.

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Clinical, Radiographic, and Pathologic Findings in Patients Undergoing Reoperation Following Radiation Therapy and Temozolomide for Newly Diagnosed Glioblastoma

imagePurpose: Patients with glioblastoma (GBM) frequently deteriorate clinically and radiographically after chemoradiation and may require repeat surgical intervention. We attempted to correlate pathologic findings with preoperative clinical characteristics and survival in patients undergoing reoperation for GBM. Materials and Methods: Patients eligible for this retrospective analysis had pathologically confirmed GBM diagnosed between 2005 and 2010, received standard radiation and temozolomide, and underwent repeat resection within 18 months of diagnosis. Results: Thirty-eight patients were identified. Median age was 56 years (range, 30 to 80 y), 55% were male, and 66% had baseline performance status ≥90%. Median survival was 16.3 months (95% confidence interval [CI], 13.3-19.8) from initial surgery. At reoperation, 21% of patients had no pathologically evident tumor. Median time from initial diagnosis to second surgery was similar in patients with and without evident tumor (8.5 vs. 8.8 mo, respectively). Patients without evident tumor tended to have a worse performance status. Median overall survival from second surgery was 7 months (95% CI, 4.2-10.1) and 9.1 months (95% CI, 2.1-25.3) for patients with and without evident tumor, respectively. Multivariate proportional hazards analysis showed a hazard ratio for death of 0.61 (95% CI, 0.25-1.49) for patients without evident tumor after adjusting for Karnofsky performance status and second surgical procedure. Conclusions: GBM patients with and without disease recurrence have similar clinical characteristics at the time of second surgical resection. Pathologic outcomes were not correlated with specific clinical or radiologic characteristics, including the time from diagnosis to reoperation. There was a trend toward improved overall survival among patients without evident tumor at reoperation.

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Predictors and Patterns of Local, Regional, and Distant Failure in Squamous Cell Carcinoma of the Vulva

imageObjective: To identify factors predicting for recurrence in vulvar cancer patients undergoing surgical treatment. Methods: We retrospectively evaluated data of consecutive patients with squamous cell vulvar cancer treated between January 1, 1990 and December 31, 2013. Basic descriptive statistics and multivariable analysis were used to design predicting models influencing outcomes. Five-year disease-free survival (DFS) and overall survival (OS) were analyzed using the Cox model. Results: The study included 101 patients affected by vulvar cancer: 64 (63%) stage I, 12 (12%) stage II, 20 (20%) stage III, and 5 (5%) stage IV. After a mean (SD) follow-up of 37.6 (22.1) months, 21 (21%) recurrences occurred. Local, regional, and distant failures were recorded in 14 (14%), 6 (6%), and 3 (3%) patients, respectively. Five-year DFS and OS were 77% and 82%, respectively. At multivariate analysis only stromal invasion >2 mm (hazard ratio: 4.9 [95% confidence interval, 1.17-21.1]; P=0.04) and extracapsular lymph node involvement (hazard ratio: 9.0 (95% confidence interval, 1.17-69.5); P=0.03) correlated with worse DFS, although no factor independently correlated with OS. Looking at factors influencing local and regional failure, we observed that stromal invasion >2 mm was the only factor predicting for local recurrence, whereas lymph node extracapsular involvement predicted for regional recurrence. Conclusions: Stromal invasion >2 mm and lymph node extracapsular spread are the most important factors predicting for local and regional failure, respectively. Studies evaluating the effectiveness of adjuvant treatment in high-risk patients are warranted.

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Dose-escalated Hypofractionated Intensity-modulated Radiation Therapy With Concurrent Chemotherapy for Inoperable or Unresectable Non-Small Cell Lung Cancer

imagePurpose: The local control of inoperable non-small cell lung cancer (NSCLC) using standard radiotherapy (RT) doses is inadequate. Dose escalation is a potential strategy to improve the local control for patients with NSCLC; however, the optimal dose required for local control in this setting is unknown. Methods and Materials: Patients with unresectable or inoperable stage II/III NSCLC with ECOG≤1 received 48 Gy in 20 daily fractions using intensity-modulated radiotherapy, followed by 1 of 3 boost dose levels: 16.8 Gy/7 (cumulative 2 Gy equivalent dose [EQD2]≅76 Gy/38), 20.0 Gy/7 (EQD2≅84 Gy/42), and 22.7 Gy/7 (EQD2≅92 Gy/46). Two cycles of cisplatin/etoposide chemotherapy were given concurrent with RT. The maximum tolerated dose was defined as the dose at which ≥30% experienced dose-limiting toxicity (any NCIC Common Terminology for Adverse Events V3.0 grade 3 or higher acute toxicity). Results: Twelve patients completed treatment with a median follow-up of 22 months (range, 7 to 48). The median age was 72 (range, 54 to 80) and 50% of patients had adenocarcinoma. Five, 3, and 4 patients were treated on dose levels 1, 2, and 3, respectively. No dose-limiting toxicity was observed. One-year local progression-free survival and overall survival estimates were 81% and 58%, respectively. Conclusions: Hypofractionated intensity-modulated radiotherapy was well tolerated and provided meaningful local control for patients with locally advanced inoperable NSCLC. The maximum tolerated dose of RT in this setting lies beyond an EQD2 of 92 Gy/46 and further dose escalation in this setting is warranted.

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Phase I Dose-Escalation Study of Weekly Paclitaxel and Cisplatin Followed by Radical Hysterectomy in Stages IB2 and IIA2 Cervical Cancer

imagePurpose: To define the optimal dose of paclitaxel combining cisplatin, as weekly neoadjuvant chemotherapy (NAC) for early-stage bulky squamous cell carcinoma of the uterine cervix. Methods: A prospective trial was conducted for International Federation of Gynecology and Obstetrics stages IB2 and IIA2 cervical squamous cell carcinoma patients with magnetic resonance imaging or positron emission tomography-defined lymph node negative. Weekly fixed-dose cisplatin (40 mg/m2) and 4-level dose escalation of paclitaxel (50, 60, 70, 80 mg/m2) for 3 courses was given and followed by radical hysterectomy and pelvic lymph node dissection (RH-PLND) 14 to 28 days later. Postoperative adjuvant therapy was tailored according to pathologic response. Results: No dose-limiting toxicity occurred. Twelve subjects were enrolled without reaching maximum tolerated dose, nor was any RH-PLND procedure delayed for >2 weeks. Pathologic response rate was 50% (complete in 2 and partial in 4). Paclitaxel dose level seemed unrelated to pathologic response. No subjects had grade ≥3 acute adverse events. Seven patients (58.3%) received postoperative radiotherapy or chemoradiation. Patients with human papillomavirus 16-negative tumor and aged 55 years and older had marginally higher risk (100%) of adjuvant radiotherapy or chemoradiation after NAC than those with human papillomavirus 16-positive or age less than 55 (P=0.081). With a median follow-up of 45.5 months, all 12 patients remained alive without disease. Conclusions: Weekly paclitaxel and cisplatin NAC for 3 courses can be tolerated with excellent short-term outcome. With the caveat of small number of patients, this study supports future phase II trials of weekly paclitaxel and cisplatin NAC for 4 to 5 cycles.

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Locally Advanced Malignant Myoepithelioma of the Parotid Gland Treated With Radiotherapy: A Case Study and Review of the BC Cancer Agency Experience

imageObjectives: Malignant myoepithelioma of salivary glands is a rare neoplasm; most arise in the parotid gland and minor salivary glands of the palate. Surgery has been the mainstay of treatment. Methods: This is case report of a patient treated with primary radical radiotherapy and retrospective review of institutional experience. Results: An 87-year-old man with locoregionally advanced malignant myoepithelioma of the parotid gland received radiotherapy alone with complete clinical response and sustained 39 months of posttreatment. Between 1981 and 2012, 15 cases of malignant myoepithelioma of the parotid were seen. Thirteen patients received surgical excision and adjuvant radiotherapy. At a median follow-up of 47 months, 12 patients were alive without recurrence, 2 died without recurrence, and 1 died with metastatic myoepithelioma. Conclusions: Durable locoregional disease control and disease-free-survival was achieved in the majority of patients. The case reported suggests radiation therapy may be an effective treatment option for inoperable cases.

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Oncologic and Functional Hazards of Obesity Among Patients With Locally Advanced Rectal Cancer Following Neoadjuvant Chemoradiation Therapy

imageObjective: Obesity is a major health concern and risk factor for colorectal cancer that may also impact cancer treatment and outcomes. Rectal cancer response to chemoradiotherapy (CXRT) is associated with long-term survival and sphincter preservation. The purpose of this study was to evaluate the impact of obesity on treatment outcomes after neoadjuvant CXRT for rectal cancer. Methods: A retrospective cohort study of patients diagnosed (1993 to 2010) with cT3-4 or cN+ (by endorectal ultrasound, computed tomography, or magnetic resonance imaging) rectal carcinoma and treated with CXRT and total mesorectal excision was performed. Patients were classified as obese (body mass index ≥30 kg/m2) or nonobese (body mass index

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Does Choline PET/CT Change the Management of Prostate Cancer Patients With Biochemical Failure?

imagePurpose: The FDA approved C-11 choline PET/computed tomography (CT) for imaging patients with recurrent prostate cancer in 2012. Subsequently, the 2014 NCCN guidelines have introduced labeled choline PET/CT in the imaging algorithm of patients with suspected recurrent disease. However, there is only scarce data on the impact of labeled choline PET/CT findings on disease management. We hypothesized that labeled-choline PET/CT studies showing local or regional recurrence or distant metastases will have a direct role in selection of appropriate patient management and improve radiation planning in patients with disease that can be controlled using this mode of therapy. Methods: This retrospective study was approved by the Tel Aviv Sourasky and Sheba Medical Center's Helsinki ethical review committees. Patient characteristics including age, PSA, stage, prior treatments, and pre-PET choline treatment recommendations based on NCCN guidelines were recorded. Patients with biochemical failure and without evidence of recurrence on physical examination or standard imaging were offered the option of additional imaging with labeled choline PET/CT. Treatment recommendations post-PET/CT were compared with pre-PET/CT ones. Pathologic confirmation was obtained before prostate retreatment. A nonparametric χ2 test was used to compare the initial and final treatment recommendations following choline PET/CT. Results: Between June 2010 and January 2014, 34 labeled-choline PET/CT studies were performed on 33 patients with biochemical failure following radical prostatectomy (RP) (n=6), radiation therapy (RT) (n=6), brachytherapy (n=2), RP+salvage prostate fossa RT (n=14), and RP+salvage prostate fossa/lymph node RT (n=6). Median PSA level before imaging was 2 ng/mL (range, 0.16 to 79). Labeled choline PET/CT showed prostate, prostate fossa, or pelvic lymph node increased uptake in 17 studies, remote metastatic disease in 9 studies, and failed to identify the cause for biochemical failure in 7 scans. PET/CT altered treatment approach in 18 of 33 (55%) patients (P=0.05). Sixteen of 27 patients (59%) treated previously with radiation were retreated with RT and delayed or eliminated androgen deprivation therapy: 1 received salvage brachytherapy, 10 received salvage pelvic lymph node or prostate fossa irradiation, 2 brachytherapy failures received salvage prostate and lymph nodes IMRT, and 3 with solitary bone metastasis were treated with radiosurgery. Eleven of 16 patients retreated responded to salvage therapy with a significant PSA response (

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