bluuebunny/crossref_metadata_2025 huggingface dataset:
Upregulation of DNA Sensors in B16.F10 Melanoma Spheroid Cells After Electrotransfer of pDNA
Authors: Znidar Katarina , Bosnjak Masa , Jesenko Tanja , Heller Loree C. , Cemazar Maja
Published: June 2018

Increased expression of cytosolic DNA sensors, a category of pattern recognition receptor, after control plasmid DNA electrotransfer was observed in our previous studies on B16.F10 murine melanoma cells. This expression was correlated with the upregulation of proinflammatory cytokines and chemokines and was associated with cell death. Here, we expanded our research to include the influence of features of cells in a 3-dimensional environment, which better represents the tumors’ organization in vivo. Our results show that lower number of cells were transfected in spheroids compared to 2-dimensional cultures, that growth was delayed after electroporation alone or after electrotransfer of plasmid DNA, and that DNA sensors DDX60, DAI/ZBP1, and p204 were upregulated 4 hours and 24 hours after electrotransfer of plasmid DNA. Moreover, the cytokines interferon β and tumor necrosis factor α were also upregulated but only 4 hours after electrotransfer of plasmid DNA. Thus, our results confirm the results obtained in 2-dimensional cell cultures demonstrating that electrotransfer of plasmid DNA to tumor cells in spheroids also upregulated cytosolic DNA sensors and cytokines.
Feasibility Study Using Propensity Score Matching Methods for the Pseudo-Common Person Equating Requirement
Authors: Hong Ickpyo , Hay Catherine C. , Reistetter Timothy A.
Published: June 2018

We tested if a propensity score (PS) matching method supports the unidimensionality assumption of the Rasch model which is critical to link similar rehabilitation instruments. We obtained 1,013 respondents from the 2009 Hispanic Established Populations for Epidemiologic Studies of the Elderly Frailty study. We used a unidimensional item pool of 10 SF-36 physical function and nine activities of daily living items. Subjects were matched based on their functionality (high and low), and exploratory factor analysis was used to test if the item pool in the matched sample holds the unidimensionality assumption. The study findings revealed that the matched sample demonstrated two distinct measurement structures with excellent model fit. This finding indicates that the PS matching did not mimic the common-person assumption. Therefore, the combination of PS matching and common-person equating method may not be appropriate to equate two rehabilitation-related instruments administered to two different groups.
The Relationship Between Health-Related Quality of Life and Anabolic Hormone Levels in Middle-Aged and Elderly Men With Prediabetes: A Cross-Sectional Study
Authors: Rabijewski Michał , Papierska Lucyna , Maksym Radosław , Tomasiuk Ryszard , Kajdy Anna , Siekierski Bogusław Paweł
Published: June 2018

The aim of this study was to compare health-related quality of life (HRQoL) between men with prediabetes (PD) and a control group as well as to investigate the relationship between HRQoL and anabolic hormones. The analysis was carried out in 176 middle-aged (40–59 years) and elderly (60 80 years) men with PD, and 184 control peers. PD was defined according the American Diabetes Association and HRQoL was assessed by the SF-36 questionnaire. Total testosterone (TT), calculated free testosterone, dehydroepiandrosterone sulfate (DHEAS), and insulin-like growth factor 1 (IGF-1) were measured. Analysis of the standardized physical and mental component summary scores (SF-36p and SF-36m) revealed that patients with PD had lower SF-36p and SF-36m than control group ( p < .02 and p < .001). Middle-aged men with PD had lower SF-36p and SF-36m than control peers, whereas elderly men with PD had lower only SF-36p. In men with PD negative correlations between glycated hemoglobin (HbA1c) and SF-35m score ( r = −0.3768; p = .02) and between HbA1c and SF-36p score ( r = −0.3453; p = .01) were reported. In middle-aged prediabetic men, SF-36p was associated with high free testosterone and low HbA1c while SF-36m with high TT and high DHEAS. In elderly patients with PD, SF-36p was associated with high TT, high IGF-1, and low HbA1c, while SF-36m correlated with high free testosterone and high DHEAS. In conclusion, PD in men is associated with decreased HRQoL in comparison with healthy men, and generally better quality of life is associated with higher testosterone, higher free testosterone, higher DHEAS, and lower HbA1c.
Intersection of Mixed Methods and Community-Based Participatory Research: A Methodological Review
Authors: DeJonckheere Melissa , Lindquist-Grantz Robin , Toraman Sinem , Haddad Kristen , Vaughn Lisa M.
Published: June 2018

Although mixed methods research (MMR) and community-based participatory research (CBPR) have been employed to investigate complex research questions to improve the reach, rigor, and relevance of research, little is understood about the intersection of the approaches. We conducted a methodological review of studies ( n = 129) using both MMR and CBPR, an advanced application we refer to as mixed methods community-based participatory research (MMCBPR). We systematically examined published MMCBPR studies to identify the methodological features and use in current research. Findings demonstrate that the components of MMR were not adequately described although some detail was provided about the use of CBPR. This study contributes to the evolution of advanced applications, and we offer recommendations for future applications of MMCBPR.
Expression signature of lysosomal-associated transmembrane protein 4B in hepatitis C virus-induced hepatocellular carcinoma
Authors: Roy Gaurav , Roy Papai , Bhattacharjee Atanu , Shahid Mudassar , Misbah Mohammad , Gupta Subash , Husain Mohammad
Published: June 2018

Introduction:

Hepatocellular carcinoma is a lethal disease worldwide and therefore the establishment of novel diagnostic biomarkers is imperative. In this study, it was hypothesized that an abnormal expression of the lysosomal-associated protein transmembrane 4 beta ( LAPTM4B) gene is crucial in the pathogenesis of hepatitis C virus-mediated hepatocellular carcinoma; hence we investigated the expression profile of LAPTM4B in hepatitis C virus-induced hepatocellular carcinoma.

Methods:

A group of 189 consecutive patients (hepatitis C virus-related hepatocellular carcinoma as tumor cases; n=93, hepatitis C virus-related cirrhotics as disease controls; n=96) opting for living donor liver transplantation as a therapeutic surgical regimen were recruited with informed consent. Additionally, paired adjacent non-tumorous tissues (n=93) obtained from cases were also included. Serum LAPTM4B protein concentrations were assessed by third-generation enzyme-linked immunosorbent assay and LAPTM4B mRNA, and protein expressions at tissue level were determined by quantitative real time reverse transcription-polymerase chain reaction (qRT-PCR) and immunohistochemistry techniques, respectively.

Results:

LAPTM4B protein concentrations in sera of patients were higher ( p<0.001) in tumor cases (1.25±0.25 ng/ml) compared to disease controls (0.53±0.28 ng/ml). Our study also depicts positive clinicopathological correlations between alpha-fetoprotein titers (b=0.65; p<0.001), quantitative hepatitis C virus RNA copies (b=0.33; p<0.001), and LAPTM4B protein concentrations, all in sera of patients. In addition, qRT-PCR and immunohistochemistry analyses revealed a significantly higher ( p<0.05) tissue LAPTM4B mRNA and protein expression, respectively, in tumor cases rather than in non-tumorous tissues and disease controls.

Conclusions:

Together, our results illustrate the LAPTM4B gene as a diagnostic biomarker in patients with hepatocellular carcinoma having documented evidence of chronic hepatitis C virus infection.
Live reality television: Care structures within the production and reception of talent shows
Authors: Hill Annette , Askanius Tina , Kondo Koko
Published: June 2018

This article focuses on production and reception practices for live reality television using critical theory and empirical research to question how producers and audiences co-create and limit live experiences. The concept of care structures is used to make visible hidden labour in the creation of mood, in particular audiences as participants in the management of live experiences. In the case of Got to Dance, there was a play off between the value and meaning of the live events as a temporary experience captured by ratings and social media, and the more enduring collective-social experience of this reality series over time.
Ultrasound determination of presence, length and diameter of the palmaris longus tendon
Authors: Johnson Christine C. , Vutescu Emil Stefan , Miller Theodore T. , Nwawka O. Kenechi , Lee Steve K. , Wolfe Scott W.
Published: June 2018

Inadvertent median nerve harvest is a devastating complication of palmaris longus harvest. Accurate assessment of palmaris longus presence and dimensions preoperatively would minimize this risk and assure safe harvest. We hypothesized that ultrasound would accurately predict palmaris longus presence, length and diameter. Seventeen cadaveric forearms were studied using a LOGIQ-E9 ultrasound. Two radiologists assessed palmaris longus presence and dimensions. Each wrist was explored, and the tendon was harvested and measured. Inter-rater reliability and agreement between measurements was assessed. The palmaris longus was present in 13 of 17 forearms. Both radiologists correctly identified the tendon and its absence (sensitivity and specificity, 100%). Ultrasound assessment of palmaris longus dimensions significantly correlated with surgical measurements. Intraclass correlation coefficient between radiologists was 0.97. We conclude that ultrasound can determine palmaris longus presence and dimensions with excellent accuracy and inter-observer reliability. Ultrasound is useful for preoperative evaluation of the palmaris longus and its use will increase patient safety.
Effect of a 6-Week Weighted Baseball Throwing Program on Pitch Velocity, Pitching Arm Biomechanics, Passive Range of Motion, and Injury Rates
Authors: Reinold Michael M. , Macrina Leonard C. , Fleisig Glenn S. , Aune Kyle , Andrews James R.
Published: June 2018

Background:

Emphasis on enhancing baseball pitch velocity has become popular, especially through weighted-ball throwing. However, little is known about the physical effects or safety of these programs. The purpose of this study was to examine the effects of training with weighted baseballs on pitch velocity, passive range of motion (PROM), muscle strength, elbow torque, and injury rates.

Hypothesis:

A 6-week weighted ball training program would result in a change in pitching biomechanical and physical characteristics.

Study Design:

Randomized controlled trial.

Level of Evidence:

Level 1.

Methods:

During the baseball offseason, 38 healthy baseball pitchers were randomized into a control group and an experimental group. Pitch velocity, shoulder and elbow PROM, shoulder strength, elbow varus torque, and shoulder internal rotation velocity were measured in both groups. The experimental group then performed a 6-week weighted ball throwing program 3 times per week using balls ranging from 2 to 32 ounces while the control group only used a 5-ounce regulation baseball. Both groups performed a strength training program. Measurements were then repeated after the 6-week period. Injuries were tracked over the 6-week training program and the subsequent baseball season. The effect of training with a weighted ball program was assessed using 2-way repeated-measures analysis of variance at an a priori significance level of P < 0.05.

Results:

Mean age, height, mass, and pretesting throwing velocity were 15.3 ± 1.2 years (range, 13-18 years), 1.73 ± 0.28 m, 68.3 ± 11 kg, and 30.3 ± 0.7 m/s, respectively. Pitch velocity showed a statistically significant increase (3.3%) in the experimental group ( P < 0.001). There was a statistically significant increase of 4.3° of shoulder external rotation in the experimental group. The overall injury rate was 24% in the experimental group. Four participants in the experimental group suffered elbow injuries, 2 during the training program and 2 in the season after training. No pitchers in the control group were injured at any time during the study.

Conclusion:

Performing a 6-week weighted ball throwing program increased pitch velocity. However, the program resulted in increased shoulder external rotation PROM and increased injury rate.

Clinical Relevance:

Although weighted-ball training may increase pitch velocity, caution is warranted because of the notable increase in injuries and physical changes observed in this cohort.
An Eye on Vision: Five Questions About Vision Screening and Eye Health—Part 2
Authors: Nottingham Chaplin P. Kay , Baldonado Kira , Cotter Susan , Moore Bruce , Bradford Geoffrey E.
Published: June 2018

Current evidence-based and best practice vision screening and eye health approaches, tools, and procedures are the result of revised national guidelines in the last 3 years and advances in research during the past 18 years. To help the busy school nurse, with little time to keep up with changes in children’s vision practices and a growing body of literature, the National Center for Children’s Vision and Eye Health at Prevent Blindness is providing answers to five questions that are often received from the field. Topical areas include (1) which numbers to record when using a 10-foot chart, (2) instrument-based screening and visual acuity, (3) screening children who wear glasses, (4) referring children who do not pass color vision deficiency screening, and (5) conducting near visual acuity screening monocularly or binocularly.
Contemporary management of ureteral strictures
Authors: Vasudevan Vinaya P , Johnson Emmanuel U , Wong Kee , Iskander Morkos , Javed Saqib , Gupta Nikhil , McCabe John E , Kavoussi Louis
Published: June 2018

Ureteral stricture disease is a luminal narrowing of the ureter leading to functional obstruction of the kidney. Treatment of strictures is mandatory to preserve and protect renal function. In recent times, the surgical management of ureteral strictures has evolved from open repair to include laparoscopic, robotic and interventional techniques. Prompt diagnosis and early first line intervention to limit obstructive complications remains the cornerstone of successful treatment. In this article, we discuss minimally invasive, endo-urological and open approaches to the repair of ureteral strictures. Open surgical repair and endoscopic techniques have traditionally been employed with varying degrees of success. The advent of laparoscopic and robotic approaches has reduced morbidity, improved cosmesis and shortened recovery time, with results that are beginning to mirror and in some cases surpass more traditional approaches.

Level of evidence: Not applicable for this multicentre audit.
Reassessing the fulfillment of alliance commitments in war
Authors: Berkemeier Molly , Fuhrmann Matthew
Published: June 2018

Leeds et al. (2000) report that military alliance commitments are honored in war around 75% of the time. We update and extend data on alliance reliability from 1816 to 2003. Our analysis reveals a lower compliance rate overall: 50%. We find a sharp disparity in alliance reliability before and after World War II. States honored their alliance commitments 66% of the time prior to 1945 but the compliance rate drops to 22% from 1945 to 2003. Moreover, the rates of fulfillment for defense pacts (41%) and nonaggression pacts (37%) are dramatically lower than offensive alliances (74%) and neutrality agreements (78%). These findings carry implications for the role of military alliances in world politics and highlight the need for more research to explain the differences that emerge before and after World War II.
The Risk of Adverse Events in Patients With Polycystic Kidney Disease With Advanced Chronic Kidney Disease
Authors: de Chickera Sonali , Akbari Ayub , Levin Adeera , Tang Mila , Brown Pierre , Djurdev Ognjenka , Biyani Mohan , Clark Edward G. , Sood Manish M.
Published: June 2018

Background:

Polycystic kidney disease (PKD) leads to progressive chronic kidney disease (CKD) with a subsequent risk of adverse events such as cardiac disease, infections, end-stage kidney disease (ESKD), and mortality.

Objectives:

To determine the risks of CKD-related adverse outcomes in patients with PKD compared with patients without PKD.

Setting:

Canadian study of prediction of death, dialysis and interim cardiovascular events (CanPREDDICT) was a prospective pan-Canadian cohort study from 2008-2013 involving 28 facilities with adjudicated outcomes.

Patients:

Adult CKD patients (estimated glomerular filtration rate [eGFR] = 15-45 mL/min/1.73 m2) under the care of a nephrologist.

Measurements:

Polycystic kidney disease as identified by the treating physician.

Methods:

Patients with PKD (PKD) and non-PKD were propensity score (PS) matched (1:4) using demographics, comorbidities, and laboratory values. We used conditional Cox proportional hazards models to examine the risk of cardiac disease (defined as coronary artery disease or congestive heart failure), infection, ESKD, or all-cause mortality in patients with PKD compared with no PKD.

Results:

Among a total of 2370 patients, 105 with PKD were matched with 416 without PKD with a baseline mean age and eGFR of 62.6 years and 27.8 mL/min, respectively. During 1680 person-years of follow time (median follow-up: 3.8 years), there were a total of 43 cardiac, 83 ESKD, 117 infectious, and 39 all-cause mortality events. PKD was associated with a higher risk of cardiac events (9.5% vs 7.9%, hazard ratio [HR] = 1.46, 95% confidence interval [CI] = 1.04-2.04) and ESKD (25.7% vs 13.5%, HR = 2.00, 95% CI = 1.33-3.01), and with similar risks for infection (21.9% vs 22.6%, HR = 1.16, 95% CI = 0.75-1.82) or all-cause mortality (6.7% vs 7.7%, HR = 0.87, 95% CI = 0.40-1.91) compared with non-PKD. There were no differences in the types of infections (urinary, respiratory, hematologic, or other) between the 2 groups ( P = .585).

Conclusions:

Patients with PKD with advanced CKD are at a potentially higher risk of ESKD and cardiac events compared with patients without PKD. These findings, if confirmed in larger cohorts, suggest that monitoring and treatment for adverse outcomes in patients with PKD, especially related to cardiac disease, may be beneficial.
Cutaneous candidiasis caused by Candida albicans in a young non-immunosuppressed patient: an unusual presentation
Authors: Palese Enzo , Nudo Maurizio , Zino Grazia , Devirgiliis Valeria , Carbotti Mattia , Cinelli Eleonora , Rodio Donatella Maria , Bressan Alessia , Prezioso Carla , Ambrosi Cecilia , Scribano Daniela , Pietropaolo Valeria , Fioriti Daniela , Panasiti Vincenzo
Published: June 2018

Candidiasis is a fungal infection caused by yeasts that belong to the genus Candida. There are over 20 species of Candida yeasts that can cause infection in humans, the most common of which is Candida albicans. Candida yeasts normally reside in the intestinal tract and can be found on mucous membranes and skin without causing infection. However, under immunocompromised conditions, Candida can cause significant infections in susceptible patients. Herein, we report a peculiar presentation of a C. albicans cutaneous infection in an immunocompetent young subject. This case widens our knowledge on the C. albicans infections both in terms of host susceptibility and cutaneous manifestations.
Fronto-Temporal Dementia, Diabetes Mellitus and Excessive Eating
Authors: Hamdy R. C. , Kinser A. , Dickerson K. , Kendall-Wilson T. , Depelteau A. , Whalen K.
Published: June 2018

Diabetes mellitus is common among older people. Hypoglycemia is a sign of poorly controlled diabetes mellitus and may lead to irritability, agitation, anxiety, hunger, and an excessive food intake, which in turn may make the control of diabetes more difficult. Excessive, inappropriate food intake is also a sign of Fronto-Temporal Dementia (behavioral variant: bvFTD). In this case study, we describe the events leading to an altercation that developed between an older diabetic patient with bvFTD and the staff in an Assisted Living Facility. His first dose of insulin was given early that morning while he was still asleep. He, subsequently, woke up feeling hungry, agitated, and irritable. This, in turn, exacerbated the hyperorality associated with bvFTD. We examine what went wrong in the patient/caregiver interaction and how this potentially catastrophic situation could have been avoided or defused.
The Acquistion of Opportunity of Shadow Education for Chinese Junior High School Student
Authors: Wang Xiaolei
Published: June 2018

The paper based on baseline data of China Education Panel Survey  (CEPS2013-2014) to analyze the differences in the opportunities of acquiring shadow education between only child and non-only child in China.This study determined that the probability of an only child acquiring shadow education is higher than that of a non-only child. Shadow education activities among only child and non-only child feature “cultivating the elites” and “advancing the backwards.” Among them, an only child can maximize the effects of “advancing the backwards” of shadow education, whereas non-only child can maximize the effects of “advancing the backwards” of shadow education. Research results of non-only children show that the higher the number of children, the more unfavorable for students to participate in shadow education activities. Furthermore, the birth order of children affects the opportunity for non-only child to acquire shadow education, whereas first-born or last-born children can acquire better shadow education.
Some Random Thoughts about Victimological Movement in the World with Special Reference to India
Authors: Chockalingam K.
Published: June 2018

Historically, priority of the criminal justice system was always to establish the guilt of the accused and provide a punishment to the offender. Even after the advent of scientific criminology, focus was on all aspects of the offender, to the complete neglect of the victim. Victim was always treated as a witness, and victim justice has been a struggle throughout the world. Many scholars and criminal justice administrators recommended urgent measures to improve the conditions of victims, particularly after the historic Report of President’s Task Force in 1982 in the USA. Since then a victimological movement emerged which culminated in the creation of UN Declaration of Basic Principles of Justice for Victims of Crime and Abuse of Power, 1985. In this article, the emergence of victimological movement, its impact and the subsequent developments in India are discussed.
A function-blocking PAR4 antibody is markedly antithrombotic in the face of a hyperreactive PAR4 variant
Authors: French Shauna L. , Thalmann Claudia , Bray Paul F. , Macdonald Lynn E. , Murphy Andrew J. , Sleeman Mark W. , Hamilton Justin R.
Published: June 2018

Key Points

A human monoclonal inhibitory PAR4 antibody is equally effective in platelets expressing the Ala120 or hyperreactive Thr120 PAR4 variant. Antibody-mediated PAR4 inhibition is markedly anti-thrombotic in human blood, independent of PAR4 genotype.
Management of peripheral arterial disease in diabetes: a national survey of podiatry practice in the United Kingdom
Authors: Normahani Pasha , Mustafa Chira , Standfield Nigel J. , Duguid Claire , Fox Martin , Jaffer Usman
Published: June 2018

Background

We aimed to investigate podiatry practice in diagnosing peripheral arterial disease (PAD) in diabetes, decision making once PAD is suspected and limitations of referral pathways.

Methods

A survey, comprising 26 questions was distributed to podiatrists across the UK via mailing lists of collaborating organizations including the College of Podiatry (UK). Response rates were estimated based on NHS workforce data. Analysis of responses from the open‐ended questions was performed using inductive content analysis.

Results

Data from 283 respondents were analyzed. Response rate for all NHS podiatrists across the UK was estimated to be 6%. For the detection of arterial disease only 18.8% (n = 49/260) of participants reported using a full combination of history, pulse palpation, Doppler and ABPI assessment. Self‐reported confidence in detecting arterial disease was highest amongst podiatrists who felt they had received adequate training compared to podiatrists who felt they had not (median 85 (IQR 75–90) vs 67 (50–77), respectively; p < 0.001) as well as those who see > 20 diabetic patients per week compared to those who see < 20 (median 80 (IQR 70–90) vs 72 (60–82.8), respectively; p < 0.001). Over one third of respondents (35.8%, n = 93/260) were aware of missed cases of PAD in the past year and 17.5% (n = 38/217) believed that this resulted in an amputation in some cases.

The survey highlighted a lack of clarity amongst podiatrists regarding referral guidelines. Additionally, 69% (n = 169/242) reported that their patients had to wait longer than 2‐weeks for specialist vascular assessment and 67.6% (n = 54/80) reported similar waits for a Duplex Ultrasound scan. There was a statistically significant variation in DUS waiting time across the UK (X2 (10, N = 80) = 21.59, p = 0.017). Inability to make a direct referral to vascular services and long delays were reported as major limitations of the referral pathway.

Conclusion

We have identified important targets for further investigation and quality improvement.
Word clustering based on POS feature for efficient twitter sentiment analysis
Authors: Wang Yili , Kim KyungTae , Lee ByungJun , Youn Hee Yong
Published: June 2018

With rapid growth of social networking service on Internet, huge amount of information are continuously generated in real time. As a result, sentiment analysis of online reviews and messages has become a popular research issue [1]. In this paper a novel modified Chi Square-based feature clustering and weighting scheme is proposed for the sentiment analysis of twitter message. Along with the part of speech tagging, the discriminability and dependency of the words in the tagged training dataset are taken into account in the clustering and weighting process. The multinomial Naïve Bayes model is also employed to handle redundant features, and the influence of emotional words is raised for maximizing the accuracy. Computer simulation with Sentiment 140 workload shows that the proposed scheme significantly outperforms four existing representative sentiment analysis schemes in terms of the accuracy regardless of the size of training and test data.
The influence of stratigraphic architecture on seismic response: Reflectivity modeling of outcropping deepwater channel units
Authors: Pemberton Erin A. L. , Stright Lisa , Fletcher Sean , Hubbard Stephen M.
Published: June 2018

The size, shape, stacking patterns, and internal architecture of deepwater deposits control reservoir fluid flow connectivity. Predicting deepwater stratigraphic architecture as a function of position along a deepwater slope from seismic-reflection data is critical for successful hydrocarbon exploration and development projects. Stratigraphic architecture from confined and weakly confined segments of a deepwater sediment-routing system is analyzed in outcrop from the Tres Pasos Formation (Upper Cretaceous), southern Chile. Outcrop observations are the basis of two geocellular models: confined channel deposits at Laguna Figueroa and weakly confined channel and scour deposits at Arroyo Picana. Key stratigraphic surfaces and facies relationships observed in outcrop are forward seismic modeled at high to low resolution to bridge the gap in subseismic scale interpretation of deepwater reservoirs and demonstrate challenges associated with identification of varied reservoir architecture. The outcrop-constrained geometry of architectural elements, their stacking arrangement, and the varied internal distribution of facies each impart a strong influence on seismic reflectivity. Key outcomes from the analysis include (1) stratigraphic architecture transitions down-paleoslope from vertically aligned low-aspect-ratio channel elements to a more weakly confined depocenter characterized by a breadth of laterally offset low- and high-aspect-ratio channel and scour elements. Seismic reflections, down to 30 Hz frequencies, record aspects of these stratigraphic changes. (2) Key seismic reflections are often comprised of multiple outcrop-constrained stratigraphic surfaces. Tuning effects result in composite seismic surfaces that are vertically offset from the known position of sedimentary units; this hinders accurate interpretation of stratigraphic surfaces from seismic-reflection data. This is particularly problematic in the weakly confined system in which shifted stratigraphic surfaces, which bound deposits characterized by numerous similar architectural elements, can alter the interpretability of sandstone connectivity within and across zones. Furthermore, misinterpretation of surfaces is problematic when they are flow barriers draped with debris flows, slumps/slides, or thin-bedded turbidites. (3) Tuning effects also impart significant control on volume-based interpretations from seismic data. In particular, calculations of gross rock volume from seismic reflection data that do not consider the tuning or architectural element stacking pattern can overestimate actual volumes by 10%–50%, with implications for reservoir prediction and hydrocarbon volume estimation.
Precision Medicine for Primary Central Nervous System Tumors: Are We There Yet?
Authors: Ippen Franziska Maria , Colman Howard , van den Bent Martin J. , Brastianos Priscilla Kaliopi
Published: June 2018

In recent years, technologic advances have increased tremendously our understanding of the molecular characteristics and genetic drivers of a variety of brain tumors. These discoveries have led to paradigm shifts in the treatment of these tumor entities and may therefore have a considerable impact on the outcome of affected patients in the near future. Here, we provide a broad overview of recently discovered clinically actionable mutations that have been identified in three different primary brain tumors: gliomas, meningiomas, and craniopharyngiomas. We furthermore highlight the diagnostic and therapeutic implications of these findings and summarize recently published and ongoing trials.
Moving From Mutation to Actionability
Authors: Colombo Ilaria , Kurnit Katherine C. , Westin Shannon N. , Oza Amit M.
Published: June 2018

The diffusion of high-throughput next-generation sequencing technologies has sustained massive parallel sequencing of tumor tissue providing a deep insight into tumor biology and advancement of personalized medicine. A substantial number of targeted agents have been investigated in gynecologic cancer and some have received U.S. Food and Drug Administration approval, like PARP inhibitors in ovarian cancer, bevacizumab in ovarian and cervical cancers, and pembrolizumab in microsatellite-unstable or mismatch repair–deficient endometrial cancer. To improve effectiveness of targeted therapy, identification of predictive biomarkers able to guide the selection of the correct drug for the correct patient is crucial. Different limitations must be addressed to favor a more rapid implementation of a genotyping approach in treatment selection, such as the possibility to easily assess tumor heterogeneity and clonal evolution along the disease trajectory and the need for innovative trial designs like adaptive or basket trials incorporating molecular features as selection criteria. A deep dive into the genomic features of exceptional responders may also favor better understanding of tumor biology, mechanism of action of a specific target agent, and identification or predictive biomarkers for subsequent tailored studies.
Telemedicine in Cancer Care
Authors: Sirintrapun S. Joseph , Lopez Ana Maria
Published: June 2018

Telemedicine uses telecommunications technology as a tool to deliver health care to populations with limited access to care. Telemedicine has been tested in multiple clinical settings, demonstrating at least equivalency to in-person care and high levels of patient and health professional satisfaction. Teleoncology has been demonstrated to improve access to care and decrease health care costs. Teleconsultations may take place in a synchronous, asynchronous, or blended format. Examples of successful teleoncology applications include cancer telegenetics, bundling of cancer-related teleapplications, remote chemotherapy supervision, symptom management, survivorship care, palliative care, and approaches to increase access to cancer clinical trials. Telepathology is critical to cancer care and may be accomplished synchronously and asynchronously for both cytology and tissue diagnoses. Mobile applications support symptom management, lifestyle modification, and medication adherence as a tool for home-based care. Telemedicine can support the oncologist with access to interactive tele-education. Teleoncology practice should maintain in-person professional standards, including documentation integrated into the patient’s electronic health record. Telemedicine training is essential to facilitate rapport, maximize engagement, and conduct an accurate virtual exam. With the appropriate attachments, the only limitation to the virtual exam is palpation. The national telehealth resource centers can provide interested clinicians with the latest information on telemedicine reimbursement, parity, and practice. To experience the gains of teleoncology, appropriate training, education, as well as paying close attention to gaps, such as those inherent in the digital divide, are essential.
Practice-Changing Developments in Stage III Melanoma: Surgery, Adjuvant Targeted Therapy, and Immunotherapy
Authors: Kudchadkar Ragini R. , Michielin Olivier , van Akkooi Alexander C. J.
Published: June 2018

In this article, we will focus on the practice-changing developments for stage III melanoma, from the use of the sentinel node (SN) biopsy to complete lymph node dissection (CLND) and upcoming adjuvant therapies. MSLT-1 (Multicenter Selective Lymphadenectomy Trial-1) was the first and only prospective randomized controlled trial to examine whether the SN biopsy has any notable melanoma-specific survival benefit (primary endpoint). MSLT-1 randomly assigned 2,001 patients to undergo either wide local excision (WLE) and an SN biopsy or WLE and nodal observation. Two prospective randomized controlled trials have examined the potential benefit for immediate CLND versus delayed CLND after sequential observation. Both the DECOG-SLT and MSLT-2 trials failed to demonstrate a notable benefit for immediate CLND; therefore, sequential follow-up with ultrasonography and a delayed CLND in the case of relapse should be considered the new standard of care. The CheckMate 238 study demonstrated a notable benefit for adjuvant nivolumab in terms of 18-month relapse-free survival (RFS) rates compared with high-dose adjuvant ipilimumab. Single-agent adjuvant BRAF inhibition has been examined and failed to improve RFS. However, the COMBI-AD study did demonstrate a substantial benefit for combination BRAF and MEK inhibition for patients with BRAF-mutated resected stage IIIA to IIIC melanoma.
Multidisciplinary Management of Oligometastatic Soft Tissue Sarcoma
Authors: Grilley-Olson Juneko E. , Webber Nicholas P. , Demos David S. , Christensen Jared D. , Kirsch David G.
Published: June 2018

Soft tissue sarcomas (STS) encompass a group of rare but heterogeneous diseases. Nevertheless, many patients, particularly those with oligometastatic disease can benefit from thoughtful multimodality evaluation and treatment regardless of the STS subtype. Here, we review surgical, interventional radiology, radiation, and chemotherapy approaches to maximize disease palliation and improve survival, including occasionally long-term disease-free survival. Surgical resection can include lung or other visceral, soft tissue and bone metastases with a goal of rendering the patient disease free. Staged resections can be appropriate, and serial resection of oligometastatic recurrent disease can be appropriate. Retrospective series suggest survival benefit from this approach, although selection bias may contribute. Interventional radiology techniques such as percutaneous thermal ablation (PTA) and arterial embolization can present nonoperative local approaches in patients who are not medically fit for surgery, surgery is too morbid, or patients who decline surgery. Similarly, radiation therapy can be delivered safely to areas that are inaccessible surgically or would result in excessive morbidity. Currently no randomized trials exist comparing interventional radiologic approaches or radiation therapy to surgery but retrospective reviews show relatively similar magnitude of benefit in terms of disease palliation and survival, although it is felt unlikely that these procedures will render a patient to long-term disease-free status. Chemotherapy has evolved recently with the addition of several new treatment options, briefly reviewed here. Importantly, if a patient sustains a good response to chemotherapy resulting in true oligometastatic disease, consideration of multimodality local therapy approaches can be considered in the appropriate patient.
Global Health Perspective in Sarcomas and Other Rare Cancers
Authors: Florou Vaia , Nascimento Antonio G. , Gulia Ashish , de Lima Lopes Gilberto
Published: June 2018

Sarcomas, rare and heterogenous malignancies that comprise less than 1% of all cancers, have poor outcomes in the metastatic and refractory setting. Their management requires a multidisciplinary approach that consists of medical and surgical oncologists, radiation oncologists, and pathologists as well as ancillary support. In addition to systemic treatments, most patients will require surgical resection and radiation therapy, which mandates the use of the latest technologies and specialized expertise. Management guidelines have been developed in high-income countries, but their applicability in low-income countries, where resources may be limited, remains a challenge. In this article, we propose the best possible evidence-based practices specifically for income-constrained settings to overcome this challenge. In addition, we review the different methods that can be used in low-income countries to access new and expensive treatments, which often times carry prohibitive costs for these areas.
Patterns of Response and Progression to Immunotherapy
Authors: Borcoman Edith , Nandikolla Amara , Long Georgina , Goel Sanjay , Le Tourneau Christophe
Published: June 2018

Patterns of response and progression to immunotherapy may differ from those observed with drugs such as chemotherapy and molecularly targeted agents. Specifically, some patients experience a response after progression that is retrospectively named pseudoprogression. This phenomenon of pseudoprogression, first reported in patients with melanoma who were treated with ipilimumab, has led to the development of immune-specific related response criteria, such as irRC (immune-related response criteria), irRECIST (immune-related RECIST), and iRECIST (immunotherapy RECIST) that allow continued treatment beyond progression. However, the rate of pseudoprogression has never exceeded 10% of patients across tumor types. Conversely, rapid progressions after immunotherapy, called hyperprogressions, were reported by three different teams in 9% to 29% of patients treated with immunotherapy. Because of the absence of control arms in these studies, it remains to be determined whether these rapid progressions reflect a detrimental effect of immunotherapy in these patients. Finally, preliminary data suggest that immunotherapy might also affect response to subsequent standard therapies. In total, given the rarity of pseudoprogressions across tumor types and the recent description of hyperprogressions, classic RECIST remains a reasonable and rational method to assess response to immunotherapy. Continuation of treatment beyond progression should be proposed only in carefully selected patients whose clinical conditions have improved and who have not experienced severe toxicities. Although there is an urgent need to identify predictive biomarkers of efficacy to immunotherapy, there is an equally urgent need to identify predictive factors of progression or possibly hyperprogression.
Latest Advances in the Diagnosis and Treatment of Large Granular Lymphocytic Leukemia
Authors: Moignet Aline , Lamy Thierry
Published: June 2018

Large granular lymphocyte (LGL) leukemia has been recognized in the World Health Organization classifications among mature T cell and natural killer cell neoplasms and is divided into three categories. Chronic T cell leukemia and natural killer cell lymphocytosis can be considered as a similar spectrum of an indolent disease characterized by cytopenias and autoimmune conditions. The last category, aggressive natural killer cell LGL leukemia is very rare, related to Epstein-Barr virus, and seen mainly in young Asian people. Clonal LGL expansion arises from chronic antigenic stimulation sustained by interleukin-15 and platelet-derived growth factor cytokine signal. Those leukemic cells are resistant to apoptosis, mainly because of constitutive activation of survival pathways including Jak/Stat, MapK, Pi3k-Akt, RasRaf-1, MEK1/ERK, sphingolipid, and NFκB. Stat3 constitutive activation is the hallmark of this lymphoproliferative disorder. Socs3 is downregulated, but no mutation could be found to explain this status. However, several somatic mutations, including Stat3, Stat5b, and tumor necrosis factor alpha–induced protein 3, have been demonstrated recently in LGL leukemia; they are identified in half of patients and cannot explain by themselves LGL leukemogenesis. Recurrent infections as a result of chronic neutropenia, anemia, and autoimmune disorders are the main complications related to LGL leukemia. Despite an indolent presentation, 10% of patients die, mainly because of infectious complications. Current treatments are based on immunosuppressive therapies. A better mechanistic understanding of LGL leukemia will allow future consideration of a personalized therapeutic approach perhaps based on Jak/Stat inhibitors, which may offer better results than current immunosuppressive therapy.
Approaches to Chronic Lymphocytic Leukemia Therapy in the Era of New Agents: The Conundrum of Many Options
Authors: Jain Nitin , Thompson Philip , Ferrajoli Alessandra , Nabhan Chadi , Mato Anthony R. , O’Brien Susan
Published: June 2018

Three small molecule inhibitors have been approved for the treatment of chronic lymphocytic leukemia (CLL) in the last 4 years. Ibrutinib, idelalisib, and venetoclax are oral agents with excellent efficacy and different toxicity profiles. Issues discussed herein include the current role for chemoimmunotherapy in CLL, the use of oral inhibitors in older patients, and the sequencing of these molecules in daily practice.
Treatment of Primary Central Nervous System Lymphoma: From Chemotherapy to Small Molecules
Authors: Mendez Joe S. , Grommes Christian
Published: June 2018

Primary central nervous system lymphoma (PCNSL) is a rare form of extranodal non-Hodgkin lymphoma that is typically confined to the brain, eyes, and cerebrospinal fluid (CSF) without evidence of systemic spread. PCNSL is an uncommon tumor, and only four randomized trials and one phase III trial have been completed so far, all in the first-line setting. The prognosis of patients with PCNSL has improved during the past few decades with the introduction of high-dose methotrexate (HD-MTX), which now serves as the backbone of all first-line treatment regimens. Despite recent progress, results after treatment are durable in half of patients, and therapy can be associated with late neurotoxicity. Novel insights into the pathophysiology of PCNSL have identified the B-cell receptor (BCR) pathway as a key mechanism in the pathogenesis of PCNSL. The use of novel agents targeting components of the BCR pathway, namely the Bruton tyrosine kinase (BTK) inhibitor ibrutinib, and immunomodulatory drugs (IMIDs) like lenalidomide and pomalidomide, has so far been limited to patients who have recurrent/refractory PCNSL with promising high response rates. Within the past 5 years, there has been a peak in clinical trials investigating small molecules and novel reagents in the recurrent/refractory setting, including immune checkpoint inhibitors, IMIDs, and BTK and PI3K/AKT/mTOR inhibitors.
Molecular Subtypes and the Evolution of Treatment Decisions in Metastatic Colorectal Cancer
Authors: Dienstmann Rodrigo , Salazar Ramon , Tabernero Josep
Published: June 2018

Colorectal cancer (CRC) has clinically relevant molecular heterogeneity at multiple levels: genomics, epigenomics, transcriptomics, and microenvironment features. Genomic events acquired during carcinogenesis remain drivers of cancer progression in the metastatic setting. For example, KRAS and NRAS mutations define a population refractory to epidermal growth factor receptor monoclonal antibodies, BRAFV600E mutations associate with poor outcomes under standard therapies and response to targeted inhibitors in combinations, and HER2 amplifications confer unique sensitivity to double HER2 blockade. Multiple rare gene alterations driving resistance to epidermal growth factor receptor monoclonal antibodies have been described, with substantial overlap in primary and acquired mechanisms, in line with a clonal selection process. In this context, sequential analysis of circulating tumor DNA has the potential to guide drug development in a treatment-refractory setting. Rare kinase fusion events and complex alterations in genes involved in DNA damage repair have been described, with emerging evidence for targetability. On the other hand, transcriptomic subtypes and pathway activation signatures have also shown prognostic and potential predictive value in metastatic CRC. These markers reflect stromal and immune microenvironment interactions with cancer cells. For example, the microsatellite instable or POLE ultramutant CRC population is particularly sensitive to immune checkpoint inhibitors, whereas tumors with a mesenchymal phenotype are characterized by activation of immunosuppressive molecules that mandate stratified development of novel immunotherapy combinations. Here, we review the expanding landscape of targetable oncogenic alterations and signatures in metastatic CRC and discuss the clinical implementation of novel molecular diagnostic tests.