bluuebunny/crossref_metadata_2025 huggingface dataset:
CD11c-targeted Delivery of DNA to Dendritic Cells Leads to cGAS- and STING-dependent Maturation
Authors: Laursen Marlene F. , Christensen Esben , Degn Laura L. T. , Jønsson Kasper , Jakobsen Martin R. , Agger Ralf , Kofod-Olsen Emil
Published: November 2017

Immunotherapeutic activation of tumor-specific T cells has proven to be an interesting approach in anticancer treatment. Particularly, anti-CTLA-4 and anti–PD-1/PD-L1 treatment looks promising, and conceivably, even better clinical results might be obtained if such treatment could be combined with boosting the existing tumor-specific T-cell response. One way to achieve this could be by increasing the level of maturation of dendritic cells locally and in the draining lymph nodes. When exposed to cancer cells, dendritic cells may spontaneously mature because of danger-associated molecular patterns derived from the tumor cells. Double-stranded DNA play a particularly important role in the activation of the dendritic cells, through engagement of intracellular DNA-sensors, and signaling through the adaptor protein STING. In the present study, we have investigated the maturational response of human monocyte-derived dendritic cells (moDC) and human monocytic THP-1 cells to targeted and untargeted DNA. We used an anti-CD11c antibody conjugated with double-stranded DNA to analyze the maturation status of human moDCs, as well as maturation using a cGAS KO and STING KO THP-1 cell maturation model. We found that dendritic cells can mature after exposure to cytoplasmic double-stranded DNA delivered through CD11c-mediated endocytosis. Moreover, we show that THP-1 cells matured using IL-4, GM-CSF, and ionomycin upregulate DC-maturation markers after CD11c-targeted delivery of double-stranded DNA. This upregulation is completely abrogated in cGAS KO and STING KO cells.
Early Therapeutic Drug Monitoring of Posaconazole Oral Suspension in Patients With Hematologic Malignancies
Authors: Suh Hyeon Jeong , Kim Inho , Cho Joo-Youn , Park Sang-In , Yoon Seo Hyun , Hwang Joo-Hee , Bae Ji Yun , Lee Jeong-Ok , Koh Youngil , Song Kyoung-Ho , Choe Pyoeng Gyun , Yu Kyung-Sang , Kim Eu Suk , Kim Hong Bin , Bang Soo-Mee , Kim Nam Joong , Song Sang Hoon , Park Wan Beom , Oh Myoung-don
Published: November 2017

Background:

Therapeutic drug monitoring (TDM) of posaconazole is usually performed 1 week after starting the drug because of its long half-life. However, previous studies showed that measuring the posaconazole plasma concentration (PPC) on day 3 is effective for predicting steady-state levels. The purpose of this study was to evaluate the relevance of early TDM (day 3) of posaconazole for achieving an optimal PPC.

Methods:

This prospective study was conducted from September 2014 to August 2016. A total of 148 patients with acute myeloid leukemia or myelodysplastic syndromes received a 200 mg posaconazole oral suspension 3 times daily for fungal prophylaxis. During the period from September 2014 to December 2015 (control group), no dose adjustment was performed on day 3. During the period from January 2016 to Aug 2016 (early TDM group), the frequency of posaconazole 200-mg administration was increased to 4 times daily in patients whose PPC on day 3 was <400 ng/mL. The cutoff value for optimal PPC on day 8 was defined as 500 ng/mL.

Results:

In 21 of 107 patients (20%) in the control group, PPC was <400 ng/mL on day 3. In 15 (71%) of these 21 patients, the PPC was suboptimal on day 8. In the early TDM group, the PPC was <400 ng/mL on day 3 in 4 of 41 patients (10%). After increasing the posaconazole administration frequency in these 4 patients, PPC was suboptimal on day 8 in 1 patient (25%). In both groups, 104 patients had a PPC of ≥500 ng/mL on day 3, but 7% (7/104) of these had a suboptimal level on day 8.

Conclusions:

Early TDM on day 3 for posaconazole suspension may help more patients achieve optimal drug levels on day 8, although TDM on day 8 is needed even in patients with optimal levels on day 3.
FUNCTIONAL AND ANATOMICAL SIGNIFICANCE OF THE ECTOPIC INNER FOVEAL LAYERS IN EYES WITH IDIOPATHIC EPIRETINAL MEMBRANES
Authors: Govetto Andrea , Virgili Gianni , Rodriguez Francisco J. , Figueroa Marta S. , Sarraf David , Hubschman Jean Pierre
Published: November 2017

Purpose:

To describe the functional and anatomical outcomes of pars plana vitrectomy with epiretinal membrane and internal limiting membrane peel in eyes with and without ectopic inner foveal layers (EIFLs).

Methods:

In this retrospective multicenter study, patients diagnosed with idiopathic epiretinal membranes who underwent pars plana vitrectomy with epiretinal membrane and internal limiting membrane peel were enrolled, with a minimum follow-up of 12 months. Preoperative and postoperative spectral domain optical coherence tomography scans were qualitatively and quantitatively evaluated. The association of the EIFL and other spectral domain optical coherence tomography parameters with preoperative and postoperative best-corrected visual acuity (BCVA) was analyzed.

Results:

One hundred eleven eyes of 107 patients were included. Preoperatively, the EIFLs were present in 56 of 111 eyes (50.4%). The presence of EIFL was significantly associated with lower preoperative and postoperative BCVA (P < 0.001). Ectopic inner foveal layer thickness was negatively correlated with preoperative BCVA (r = 0.58, P < 0.001). Postoperatively, the EIFL persisted in 51 of 56 eyes (91%) with Stage 3 and 4 epiretinal membranes. Ectopic inner foveal layer thickness decreased significantly after surgery (P < 0.001), but postoperative EIFL thinning had no direct effect on postoperative change in BCVA. At 12 months from surgery, EIFL thickness maintained a significant negative correlation with BCVA (r = 0.55, P < 0.001).

Conclusion:

The presence of EIFL should be considered a negative prognostic factor for postoperative anatomical and functional recovery.
RETINAL PIGMENT EPITHELIUM–CHOROID GRAFT WITH A PERIPHERAL RETINOTOMY FOR EXUDATIVE AGE-RELATED MACULAR DEGENERATION
Authors: van Romunde Saskia H. M. , Polito Antonio , Peroglio Deiro Antonio , Guerriero Massimo , Pertile Grazia
Published: November 2017

Purpose:

To investigate the long-term outcome of autologous retinal pigment epithelium –choroid transplantation with a peripheral retinotomy for exudative age-related macular degeneration.

Methods:

In a retrospective study, we selected all patients who underwent a retinal pigment epithelium–choroid transplantation from 2007 through 2013. Exclusion criteria were age <60 years, <12 months of follow-up, and retinal pigment epithelium–choroid graft for other diseases than age-related macular degeneration. The main outcome measure was best-corrected visual acuity converted into logarithm of the minimum angle of resolution.

Results:

In this study, 81 patients were included with a mean follow-up of 38 months (SD = 19). Median best-corrected visual acuity improved from 1.30 logarithm of the minimum angle of resolution (20/400 Snellen) to 0.90 logarithm of the minimum angle of resolution (20/160 Snellen) 1 year after surgery (P < 0.001). A ≥3-line gain was achieved in 43 patients (53%) 1 year postoperatively and 37 patients (46%) preserved their visual gain until last visit. Of 4 patients with an 8-year follow-up, 3 patients had a ≥6-line gain at last visit. Severe complications were submacular hemorrhage (n = 8, 10%), macular hole (n = 6, 7%), and proliferative vitreoretinopathy (n = 3, 4%).

Conclusion:

Best-corrected visual acuity improved significantly after retinal pigment epithelium–choroid transplantation in patients with age-related macular degeneration and preservation of visual gain was possible in the long term.
RELIABILITY OF CONFOCAL WHITE-LIGHT FUNDUS IMAGING FOR MEASUREMENT OF RETINA PIGMENT EPITHELIAL ATROPHY IN AGE-RELATED MACULAR DEGENERATION
Authors: Lei Jianqin , Al-Sheikh Mayss , Shi Yue , Uji Akihito , Fan Wenying , Balasubramanian Siva , Sadda SriniVas R.
Published: November 2017

Purpose:

To assess the reproducibility of confocal white-light color fundus photography (C-CFP) for the measurement of retinal pigment epithelial atrophy in comparison with confocal blue-light fundus autofluorescence (FAF) imaging and flash color fundus photography (F-CFP).

Methods:

In this prospective study, eyes with age-related macular degeneration associated with evidence of retinal pigment epithelial atrophy were imaged by C-CFP, F-CFP, and FAF. Intergrader reproducibility of each modality was assessed by comparison of manual measurements by two expert graders.

Results:

The mean areas of atrophy measured by the 2 graders were 6.67 ± 6.39, 6.35 ± 6.13, and 6.07 ± 5.48 mm2 for FAF, C-CFP, and F-CFP, respectively. The mean differences between the 2 graders in measuring the atrophic areas were 0.52, 0.69, and 1.62 mm2 for the three modalities. The intraclass correlation coefficient between the 2 graders for each modality was 0.998, 0.990, and 0.961, respectively.

Conclusion:

Measurements of atrophy from C-CFP were similar to those obtained by FAF and F-CFP. The grading reproducibility for C-CFP, however, was better than that for F-CFP and approached the level of FAF imaging. The use of C-CFP as a tool for quantitatively monitoring atrophic age-related macular degeneration lesions warrants further study, particularly in the context of clinical trials.
SCLERAL PITS IN CHOROIDEREMIA
Authors: Al-Qahtani Abdullah A. , Ba-Ali Shakoor , Alabduljalil Talal , Coyner Aaron S. , Patel Rachel C. , Weleber Richard G. , Girach Aniz , Christensen Søren K. , Larsen Michael , Pennesi Mark E. , Yang Paul
Published: November 2017

Purpose:

We report a novel finding on spectral domain optical coherence tomography in patients with choroideremia, which we describe as scleral pits (SCPs).

Methods:

Cross-sectional observational case series of 36 patients with choroideremia, who underwent ophthalmic examination and multimodal imaging, including optical coherence tomography of the macula. Optical coherence tomography images were reviewed for SCP, which were defined as discrete tracts of hyporeflectivity that traverse the sclera with or without the involvement of Bruch membrane, retinal pigment epithelium, and retina. Unpaired two-tailed t-test with Welch correction was used for statistical analysis.

Results:

Of the 36 patients, 19 had SCP in at least one eye. Scleral pits were confined to areas of advanced chorioretinal degeneration and never involved the foveola. Type 1 SCP affected only the sclera, whereas Type 2 SCP also involved the Bruch membrane and the retinal pigment epithelium. Type 3 SCP additionally had a full-thickness retinal defect. Patients with SCP were significantly older (51 ± 2 vs. 33 ± 4 years; P < 0.05) and had lower best-corrected visual acuity (20/160 vs. 20/30 or 0.9 ± 0.2 vs. 0.2 ± 0.07 logarithm of the minimum angle of resolution; P < 0.05) than patients without SCP. Patients with SCP had a greater myopic refractive error compared with patients without SCP (−2.6 ± 0.5 vs. −0.3 ± 0.5D; P < 0.05), but there was no significant correlation between the number of SCPs with refraction. Short posterior ciliary arteries were observed to enter the eye through one Type 3 SCP.

Conclusion:

Scleral pits are, to the best of our knowledge, a novel optical coherence tomography finding in advanced choroideremia that likely represents the abnormal juxtaposition of penetrating short posterior ciliary arteries with the retina.
Effect of Continuous Systemic Administration of Esmolol on Intraocular Pressure During Surgery in a Sustained Steep Trendelenburg Position
Authors: Joo Jin , Kim Jiyoung , Lee Jaemin
Published: November 2017

Purpose:

To investigate the effects of continuous systemic administration of esmolol on intraocular pressure (IOP) during laparoscopic and robotic surgeries for recto-sigmoid cancer in a steep Trendelenburg position.

Materials and Methods:

A total of 50 patients undergoing laparoscopic surgery in a steep Trendelenburg position were included. Patients in the esmolol (E) group received a 0.25 mg/kg IV loading dose of esmolol before anesthesia, followed by an infusion of 15 μg/kg/min throughout the operation. Patients in the saline (S) group were infused with the same volume of normal saline. IOP and ocular perfusion pressure were measured 16 times: before anesthetic induction (T1), before administration of the study drug (T2), after administration of anesthetic induction agents (T3), after tracheal intubation (T4), 1, 3, 5, and 10 minutes after tracheal intubation (T5-T8), immediately after intraperitoneal CO2 insufflation (T9), immediately after the steep Trendelenburg position (T10), 1, 2, and 4 hours after the steep Trendelenburg position (T11-T13), just before the supine position (T14), and 10 and 30 minutes after the supine position (T15, T16).

Results:

The IOP increased markedly after adopting the steep Trendelenburg position, reaching 28.8±4.4 mm Hg in group S. The IOP at T13 in group S was ∼5.7 mm Hg higher than in group E. The IOP at T13 was ∼10.6 mm Hg higher than in T1 in group S, but only ∼4.4 mm Hg higher than in group E.

Conclusions:

Continuous systemic administration of esmolol can alleviate the increase in IOP during a sustained steep Trendelenburg position without adverse cardiovascular effects.
The Short-term Effect of Subtenon Sponge Application Versus Subtenon Irrigation of Mitomycin-C on the Outcomes of Trabeculectomy With Ex-PRESS Glaucoma Filtration Device: A Randomized Trial
Authors: Quist Michael S. , Brown Ninita , Bicket Amanda K. , Herndon Leon W.
Published: November 2017

Purpose:

Traditionally, during trabeculectomy, Mitomycin-C (MMC) is applied to the tissues using surgical sponges. However, alternate modes of application exist. This study assessed the success rates, complication rates, final intraocular pressure (IOP), and bleb characteristics between patients receiving subtenon MMC application by sponge versus irrigation.

Patients and Methods:

A total of 100 patients with glaucoma were enrolled and each was randomized to 1 of the 2 treatment groups. Patients underwent trabeculectomy with Ex-PRESS shunt and MMC placement and were followed for 6 months. Complication rates assessed included bleb failure, bleb leaks, bleb encapsulation, and hypotony, amongst others. Additional factors evaluated included bleb morphology, glaucoma drop usage, Fluorouracil (5-FU) application, bleb revision, and subsequent glaucoma surgery.

Results:

The irrigation method provided greater IOP lowering effects (P=0.03); correspondingly the irrigation group had higher rates of hypotony (P=0.03) but with no significant consequences. Patients who had trabeculectomy/Ex-PRESS alone had greater IOP reduction than those who had concurrent cataract surgery (P<0.001). The sponge group had higher rates of 5-FU use (P=0.007) and higher reoperation rates (P=0.02) when compared with the irrigation group. Success was defined as achieving 4 mm Hg≤IOP≤15 mm Hg without any anatomical bleb failure or subsequent glaucoma surgery. The overall success rate was 87%.

Conclusions:

Application of subtenon MMC by irrigation seems to provide improved short-term outcomes compared with application with sponges. With a similar safety profile, the irrigation method provides better IOP control, and decreases the need for further clinical/surgical intervention in the short-term after trabeculectomy. Longer-term studies will be useful in analyzing if these differences persist with time.
A Comparison of Retrobulbar Versus Topical Anesthesia in Trabeculectomy and Aqueous Shunt Surgery
Authors: Theventhiran Alex , Shabsigh Muhammad , De Moraes Carlos Gustavo , Cioffi George A. , Kamel Mohammed , Blumberg Dana , Al-Aswad Lama A.
Published: November 2017

Purpose:

The purpose of this study was to compare the required supplemental anesthesia and postoperative patient pain score in individuals undergoing glaucoma surgery under topical anesthesia (TA) versus retrobulbar anesthesia (RB).

Materials and Methods:

A retrospective, interventional, comparative cohort study of 261 eyes of 225 patients undergoing glaucoma and combined glaucoma with cataract surgery were included in the study. The main outcome measures were the amount of supplemental, systemic intraoperative anesthesia used and the postoperative pain scale between patients undergoing TA versus RB anesthesia. A secondary analysis was performed between combined glaucoma and cataract surgery versus glaucoma surgery alone.

Results:

About 6.2% patients complained of pain after glaucoma surgery (8.1% among TA group and 3.1% among RB group; P=0.049). Overall, pain tended to be mild with a mean score of 0.32 of 10 for TA and 0.08 of 10 for RB (P=0.027). The amount of IV anesthetics used intraoperatively was lower in the RB anesthesia compared with the TA group (midazolam, P=0.042; fentanyl, P<0.001; propofol, P<0.001). In addition, patients undergoing RB anesthesia were less likely to use postoperative pain medication (P<0.001). There was no difference in pain score (P=0.707) or in the amount of IV anesthetics (all P>0.350) between eyes undergoing combined versus glaucoma surgery alone.

Conclusions:

Although supplemental anesthesia and pain scores were statistically increased in the topical group, the prevalence and the severity of pain was low. Therefore, TA is feasible and a reasonable option for glaucoma surgery. Furthermore, this conclusion applies when glaucoma surgery is performed alone or in combination with the other eye surgery.
Multimodal Treatment of Rhinocerebral Mucormycosis in a Pediatric Patient With Relapsed Pre-B Acute Lymphoblastic Leukemia
Authors: Dworsky Zephyr D. , Bradley John S. , Brigger Matthew T. , Pong Alice L. , Kuo Dennis John
Published: November 2017

A 17-year-old girl developed invasive rhinocerebral mucormycosis during intensive re-induction chemotherapy for relapsed pre-B acute lymphoblastic leukemia. Due to the high case fatality rate for invasive mucormycosis in profoundly immunosuppressed patients, an aggressive treatment regimen was pursued. In addition to the standard of care treatments with intravenous amphotericin and aggressive surgical debridements, she received intraventricular amphotericin to the brain via an Ommaya reservoir, hyperbaric oxygen treatments, filgrastim, intravenous immunoglobulin and antifungal in vitro synergy testing to allow for more targeted antifungal therapy with the addition of micafungin. After a 3-month treatment course, it was determined that her mucormycosis was under appropriate control, allowing her to continue treatment for her leukemia with hematopoietic stem cell transplant with a plan for continued intravenous antifungal therapy through engraftment.
Early Childhood Neurodevelopmental Outcomes in Infants Exposed to Infectious Syphilis In Utero
Authors: Verghese Valsan P. , Hendson Leonora , Singh Ameeta , Guenette Tamara , Gratrix Jennifer , Robinson Joan L.
Published: November 2017

Background:

There are minimal neurodevelopmental follow-up data for infants exposed to syphilis in utero.

Methods:

This is an inception cohort study of infants exposed to syphilis in utero. We reviewed women with reactive syphilis serology in pregnancy or at delivery in Edmonton (Canada), 2002 through 2010 and describe the neurodevelopmental outcomes of children with and without congenital syphilis.

Results:

There were 39 births to women with reactive syphilis serology, 9 of whom had late latent syphilis (n = 4), stillbirths (n = 2) or early neonatal deaths (n = 3), leaving 30 survivors of which 11 with and 7 without congenital syphilis had neurodevelopmental assessment. Those with congenital syphilis were all born to women with inadequate syphilis treatment before delivery. Neurodevelopmental impairment was documented in 3 of 11 (27%) infants with congenital syphilis and one of 7 (14%) without congenital syphilis with speech language delays in 4 of 11 (36%) with congenital syphilis and 3 of 7 (42%) without congenital syphilis.

Conclusions:

Infants born to mothers with reactive syphilis serology during pregnancy are at high risk for neurodevelopmental impairment, whether or not they have congenital syphilis, so should all be offered neurodevelopmental assessments and early referral for services as required.
Race, Income and Insurance Status Affect Neonatal Sepsis Mortality and Healthcare Resource Utilization
Authors: Bohanon Fredrick J. , Nunez Lopez Omar , Adhikari Deepak , Mehta Hemalkumar B. , Rojas-Khalil Yesenia , Bowen-Jallow Kanika A. , Radhakrishnan Ravi S.
Published: November 2017

Background:

Socioeconomic disparities negatively impact neonatal health. The influence of sociodemographic disparities on neonatal sepsis is understudied. We examined the association of insurance payer status, income, race and gender on neonatal sepsis mortality and healthcare resource utilization.

Methods:

We used the Kid’s Inpatient Database, a nationwide population-based survey from 2006, 2009 and 2012. Neonates diagnosed with sepsis were included in the study. Multivariable logistic regression (mortality) and multivariable linear regression (length of stay and total hospital costs) were constructed to determine the association of patient and hospital characteristics.

Results:

Our study cohort included a weighted sample of 160,677 septic neonates. Several sociodemographic disparities significantly increased mortality. Self-pay patients had increased mortality (odds ratio 3.26 [95% confidence interval: 2.60–4.08]), decreased length of stay (−2.49 ± 0.31 days, P < 0.0001) and total cost (−$5015.50 ± 783.15, P < 0.0001) compared with privately insured neonates. Additionally, low household income increased odds of death compared with the most affluent households (odds ratio 1.19 [95% confidence interval: 1.05–1.35]). Moreover, Black neonates had significantly decreased length of stay (−0.86 ± 0.25, P = 0.0005) compared with White neonates.

Conclusions:

This study identified specific socioeconomic disparities that increased odds of death and increased healthcare resource utilization. Moreover, this study provides specific societal targets to address to reduce neonatal sepsis mortality in the United States.
Ischemic stroke in liver cirrhosis: epidemiology, risk factors, and in-hospital outcomes
Authors: Zhang Xintong , Qi Xingshun , Yoshida Eric M , Méndez-Sánchez Nahum , Hou Feifei , Deng Han , Wang Xiaoxi , Qiu Jing , He Chao , Wang Shuang , Guo Xiaozhong
Published: November 2017

Background and aims

Patients with cirrhosis are reportedly more prone to develop hemorrhagic stroke, thereby increasing the risk of death. However, the effect of ischemic stroke on liver diseases remains unclear. In addition, few studies have explored the risk factors for ischemic stroke in patients with liver cirrhosis. Our study aimed to explore the epidemiology, risk factors, and in-hospital outcomes of ischemic stroke in a large cohort of hospitalized patients with cirrhosis.

Patients and methods

In this single-center observational study, we retrospectively reviewed the medical records of patients with liver cirrhosis admitted to our hospital from January 2011 to June 2014. A diagnosis of ischemic stroke was further identified.

Results

Of the 2444 patients with liver cirrhosis, 160 had ischemic stroke, including 128 patients with previous ischemic stroke and 32 patients with new-onset ischemic stroke during their hospitalizations. Compared with patients with cirrhosis without ischemic stroke, those with ischemic stroke were significantly older; had a significantly higher proportion of arterial hypertension and a significantly lower proportion of hepatitis B virus infection; had significantly higher white blood cell, platelet, blood urea nitrogen, and triglyceride levels; and had significantly lower alanine aminotransferase and aspartate aminotransferase levels and prothrombin time. The in-hospital mortality was significantly higher in patients with ischemic stroke than in those without [8.80% (14/160) vs. 3.2% (72/2284), P=0.001].

Conclusion

Ischemic stroke was often observed in patients with cirrhosis, and it significantly increased the in-hospital mortality. The association of inflammation, coagulation disorders, and viral hepatitis with development of ischemic stroke in liver cirrhosis should be further evaluated in prospective cohort studies.
Predicting High Health Care Resource Utilization in a Single-payer Public Health Care System
Authors: Rosella Laura C. , Kornas Kathy , Yao Zhan , Manuel Douglas G. , Bornbaum Catherine , Fransoo Randall , Stukel Therese
Published: November 2017

Background:

A large proportion of health care spending is incurred by a small proportion of the population. Population-based health planning tools that consider both the clinical and upstream determinants of high resource users (HRU) of the health system are lacking.

Objective:

To develop and validate the High Resource User Population Risk Tool (HRUPoRT), a predictive model of adults that will become the top 5% of health care users over a 5-year period, based on self-reported clinical, sociodemographic, and health behavioral predictors in population survey data.

Research Design:

The HRUPoRT model was developed in a prospective cohort design using the combined 2005 and 2007/2008 Canadian Community Health Surveys (CCHS) (N=58,617), and validated using the external 2009/2010 CCHS cohort (N=28,721). Health care utilization for each of the 5 years following CCHS interview date were determined by applying a person-centered costing algorithm to the linked health administrative databases. Discrimination and calibration of the model were assessed using c-statistic and Hosmer-Lemeshow (HL) χ2 statistic.

Results:

The best prediction model for 5-year transition to HRU status included 12 predictors and had good discrimination (c-statistic=0.8213) and calibration (HL χ2=18.71) in the development cohort. The model performed similarly in the validation cohort (c-statistic=0.8171; HL χ2=19.95). The strongest predictors in the HRUPoRT model were age, perceived general health, and body mass index.

Conclusions:

HRUPoRT can accurately project the proportion of individuals in the population that will become a HRU over 5 years. HRUPoRT can be applied to inform health resource planning and prevention strategies at the community level.
Pediatric palliative oncology: the state of the science and art of caring for children with cancer
Authors: Snaman Jennifer M. , Kaye Erica C. , Baker Justin N. , Wolfe Joanne
Published: November 2017

Purpose of review

Pediatric palliative oncology (PPO) is an emerging field that integrates the principles of palliative care early into the illness trajectory of children with cancer. PPO providers work with interdisciplinary clinicians to provide optimal medical and psychosocial care to children with cancer and their families. Ongoing advances in the field of pediatric oncology, including new treatment options for progressive cancers, necessitate the early integration of palliative care tenets including holistic care, high-quality communication, and assessment and management of refractory symptoms.

Recent findings

Research in this emerging field has expanded dramatically over the past several years. This review will focus on advancements within several key areas of the field, specifically regarding investigation of the communication needs and preferences of patients and families, exploration of educational initiatives and interventions to teach PPO principles to clinicians, study of patient-reported and parent-reported tools to better assess and manage refractory symptoms, and development of novel models to integrate palliative care within pediatric oncology.

Research findings in the field of PPO, concurrent with advances in the treatment of pediatric cancer, may help improve survival and quality of life for children with cancer.
Metagenomics in pediatrics: using a shotgun approach to diagnose infections
Authors: Bender Jeffrey M. , Dien Bard Jennifer
Published: November 2017

Purpose of review

With the advent of novel massively parallel sequencing technologies and bioinformatic processing capabilities, clinical applications of metagenomic studies are rapidly being integrated into medicine. Through this paper, we hope to introduce this powerful new tool to clinicians caring for children.

Recent findings

Very few studies have looked at metagenomic applications in children. The ability to perform these types of massive sequencing projects was not possible as little as 7 years ago.

Metagenomics is defined as the study of all genetic material within a given sample. Novel sequencing and analysis approaches allow for unbiased assays to identify pathogens missed by targeted sequencing and culture methods. Although not widely available yet, metagenomic studies have been used to diagnose pediatric infections, identify resistance genes in clinical samples, and characterize outbreaks. Although cost and turnaround time have limited its application in clinical laboratories to date, novel platforms and increasing comfort with these techniques continue to push diagnostic metagenomics into clinical pediatric medicine. Much work in this field is yet to be done. That being said, we feel that pediatric clinicians will be using metagenomic techniques in the care of children with increasing frequency in the near future.
The Efficacy of Oral Vitamin B12 Replacement for Nutritional Vitamin B12 Deficiency
Authors: Sezer Rabia G. , Bozaykut Abdulkadir , Akoğlu Handan A. , Özdemir Gül N.
Published: November 2017

Standard treatment of vitamin B12 deficiency has not been well established in childhood, the ideal amount of supplemental vitamin B12 is not clear. Vitamin B12 deficiency is classically treated with intramuscular injections. In this study, we aimed to investigate the efficacy of oral therapy in children with vitamin B12 deficiency. Patients with serum cobalamin concentrations <300 pg/mL aged between 6 months to 18 years were included in this prospective study. Children were treated orally either with a combination of multivitamin tablet daily or vitamin B12 ampules. Serum specimens were obtained at the end of first and third months of treatment for vitamin B12 levels. A total of 79 patients were included in the study. The mean pretreatment vitamin B12 level increased from 182±47.6 pg/mL to 482±318 pg/mL after 1 month of treatment in the whole cohort. Comparison of the pretreatment vitamin B12 levels with first and third month posttreatment values showed significant difference (P-value, 0.001 and 0.028, respectively). In this study, oral cyanocobalamin was found effective for the treatment of vitamin B12 deficiency in children.
Viral DNAemia and Immune Suppression in Pediatric Sepsis
Authors: Davila Sam , Halstead E. Scott , Hall Mark W. , Doctor Allan , Telford Russell , Holubkov Richard , Carcillo Joseph A. , Storch Gregory A.
Published: November 2017

Objectives:

Demonstrate that DNA viremia is common in pediatric sepsis and quantitate its associations with host immune function and secondary infection risk.

Design:

Retrospective analysis of a prospective cohort study.

Patients:

Seventy-three children admitted with sepsis-induced organ failure.

Interventions:

None.

Measurements and Main results:

This study was performed as an ancillary investigation to a single-center prospective study of children with severe sepsis. Longitudinally collected, batched, frozen plasma was examined using real time–polymerase chain reaction for the presence of cytomegalovirus, Epstein-Barr virus, herpes simplex virus, human herpes virus-6, torque teno virus, and adenovirus DNA. Innate immune function was also measured longitudinally via quantification of ex vivo lipopolysaccharide -induced tumor necrosis factor-α production capacity. Viral DNAemia with a virus other than torque teno virus was detected in 28 of 73 subjects (38%) and included cytomegalovirus 5%, Epstein-Barr virus 11%, herpes simplex virus 4%, human herpes virus-6 8%, and adenovirus 26%. In addition, torque teno virus was detected in 89%. Epstein-Barr virus DNAemia was associated with preexisting immune suppression (p = 0.007) Viral DNAemia was associated with preexisting immune suppression and high risk for the subsequent development of secondary infection (p < 0.05 for both). Subjects with viral DNAemia had lower innate immune function over time compared with those who were virus negative (p < 0.05).

Conclusions:

DNAemia from multiple viruses can be detected in septic children and is strongly associated with preexisting immune suppression and secondary infection risk. The role of DNA viruses in the perpetuation of impaired host defense in this setting should be the subject of prospective study.
Strategies for Prevention and Management of Bleeding Following Pediatric Cardiac Surgery on Cardiopulmonary Bypass: A Scoping Review
Authors: Siemens Kristina , Sangaran Dilanee P. , Hunt Beverley J. , Murdoch Ian A. , Tibby Shane M.
Published: November 2017

Objective:

We aimed to systematically describe, via a scoping review, the literature reporting strategies for prevention and management of mediastinal bleeding post pediatric cardiopulmonary bypass surgery.

Data Sources:

MEDLINE, EMBASE, PubMed, and Cochrane CENTRAL Register.

Study Selection:

Two authors independently screened publications from 1980 to 2016 reporting the effect of therapeutic interventions on bleeding-related postoperative outcomes, including mediastinal drain loss, transfusion, chest re-exploration rate, and coagulation variables. Inclusions: less than 18 years, cardiac surgery on cardiopulmonary bypass.

Data Extraction:

Data from eligible studies were extracted using a standard data collection sheet.

Data Synthesis:

Overall, 299 of 7,434 screened articles were included, with observational studies being almost twice as common (n= 187, 63%) than controlled trials (n= 112, 38%). The most frequently evaluated interventions were antifibrinolytic drugs (75 studies, 25%), blood products (59 studies, 20%), point-of-care testing (47 studies, 16%), and cardiopulmonary bypass circuit modifications (46 studies, 15%). The publication rate for controlled trials remained constant over time (4–6/yr); however, trials were small (median participants, 51; interquartile range, 57) and overwhelmingly single center (98%). Controlled trials originated from 22 countries, with the United States, India, and Germany accounting for 50%. The commonest outcomes were mediastinal blood loss and transfusion requirements; however, these were defined inconsistently (blood loss being reported over nine different time periods). The majority of trials were aimed at bleeding prevention (98%) rather than treatment (10%), nine studies assessed both.

Conclusions:

Overall, this review demonstrates small trial sizes, low level of evidence, and marked heterogeneity of reported endpoints in the included studies. The need for more, higher quality studies reporting clinically relevant, comparable outcomes is highlighted. Emerging fields such as the use of coagulation factor concentrates, goal-directed guidelines, and anti-inflammatory therapies appear to be of particular interest. This scoping review can potentially guide future trial design and form the basis for therapy-specific systematic reviews.
Advances in the Genetics and Biology of Pancreatic Cancer
Authors: Aguirre Andrew J. , Collisson Eric A.
Published: November 2017

Pancreatic ductal adenocarcinoma (PDA) remains one of the most devastating diagnoses in modern medicine. While the clinical management of the disease has improved, the complex biologic underpinnings of PDA enable both its aggressive nature and slow clinical translational progress. In this review, we provide an overview of the key features of PDA genetics and biology, highlighting translational challenges and providing a framework for improved diagnostic and therapeutic approaches.
Symptom Management and Palliative Care in Pancreatic Cancer
Authors: Rabow Michael W. , Petzel Maria Q.B. , Adkins Sarah H.
Published: November 2017

Evidence documents the benefits of palliative care to ameliorate the symptoms of pancreatic cancer as well as those from its treatment. Professional organizations now recommend palliative care for all patients with pancreatic cancer early in the course of illness and concurrently with active treatment. Scrupulous symptom management as well as sensitive communication and advance care planning allow oncologists to provide “primary palliative care” and to care well for patients with pancreatic cancer throughout the course of their illness.
The Treatment Cascade in Children With Unsuppressed Viral Load—A Reality Check in Rural Lesotho, Southern Africa
Authors: Lejone Thabo Ishmael , Ringera Isaac , Cheleboi Molisana , Wagner Sarah , Muhairwe Josephine , Klimkait Thomas , Labhardt Niklaus D.
Published: November 2017

Background:

As per the guidelines of the World Health Organization, HIV-infected children who do not achieve viral suppression while under antiretroviral therapy (ART) receive enhanced adherence counseling (EAC) with follow-up viral load (VL). A persisting unsuppressed VL after EAC triggers switch to a second-line regimen. We describe the care cascade of children with unsuppressed VL while taking ART.

Methods:

Children, aged <16 years, on first-line ART for ≥6 months with unsuppressed VL (≥80 copies/mL) at first measurement were enrolled. As per guidelines, children/caregivers received EAC and a follow-up VL after 3 months, whereas those with persisting viremia despite good adherence were eligible for switching to second-line. Eighteen months after the first unsuppressed VL, outcomes were assessed.

Results:

Of 191 children receiving a first-time VL in May/June 2014, 53 (28%) had unsuppressed viremia. The care cascade of these 53 children was as follows: 49 (92%) received EAC and a follow-up VL in October 2014 (1 died, 3 lost to follow-up). 36/49 (73%) stayed unsuppressed, but only 24 were switched to second-line. At 18-months follow-up, 10 (19%) were retained in care with suppressed VL, 26 were retained with ongoing viremia (49%), 2 (4%) had died, and 15 (28%) had no VL documentation.

Conclusions:

Only 1 of 5 children with unsuppressed initial VL under ART was retained in care and virally suppressed at 18 months of follow-up. ART programs must increase the focus onto the extremely vulnerable care cascade in children with unsuppressed VL.
Patterns of Coronary Calcification and Their Impact on the Diagnostic Accuracy of Computed Tomography Coronary Angiography
Authors: Noll Dariusz , Kruk Mariusz , Demkow Marcin , Pręgowski Jerzy , Kaczmarska Edyta , Kryczka Karolina , Pracoń Radosław , Dzielińska Zofia , Śleszycka Justyna , Witkowski Adam , Rużyłło Witold , Kępka Cezary
Published: November 2017

Objective

Despite coronary calcifications being a major factor affecting the diagnostic accuracy of coronary computed tomography angiography (CTA), there is a lack of established criteria for categorizing calcifications. We aimed to evaluate patterns of coronary calcification based on quantitative radiodensity and size parameters to provide coronary calcium categories and assess their impact on the accuracy of coronary CTA.

Methods and Results

We analyzed length, maximum thickness, volume, mean density, and maximum density of coronary calcium and divided each of these parameters into tertiles. Subsequently, we summarized the tertiles for each individual calcification and divided them into 3 equal groups of: mild, moderate, and severe calcification. The accuracy of coronary CTA was defined as the difference between the measurements obtained on coronary CTA versus the reference of intravascular ultrasound (IVUS). We evaluated 252 coronary calcifications within 97 arteries of 60 patients. There was an expected increase in size and density values for mild versus moderate versus severe calcifications, but there was no difference in IVUS measured minimum lumen area among the 3 groups. Of note, coronary CTA significantly underestimated IVUS minimum lumen area measurement by 1.2 ± 1.6 mm2 (14.6 ± 23.1%, P < 0.001) for severe calcifications and by 0.5 ± 2.0 mm2 (3.7 ± 32.1%, P = 0.021) for moderate calcifications. Within mild calcifications, the difference was not significant.

Conclusion

Based on their dimensional and radiodensity characteristics, our analysis revealed patterns of individual coronary artery calcifications that affected the accuracy of coronary CTA measurements; coronary CTA inaccuracy was associated with the presence of moderate or severe calcifications, but not mild calcifications.
Multifunctional Assessment of Non–Small Cell Lung Cancer
Authors: Calandriello Lucio , Larici Anna Rita , Leccisotti Lucia , del Ciello Annemilia , Sica Giuliano , Infante Amato , Congedo Maria Teresa , Poscia Andrea , Giordano Alessandro , Bonomo Lorenzo
Published: November 2017

Purpose

The aim of this study was to investigate the relationship between whole-tumor CT perfusion and FDG PET/CT parameters in non–small cell lung cancer (NSCLC).

Methods

Twenty-five patients with NSCLC were prospectively included. CT perfusion parameters calculated were blood flow (BF), blood volume (BV), mean transit time, and peak enhancement intensity. SUVmax, SUVpeak, SUVmean, metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were evaluated for PET/CT. Tumor diameter and volume were measured, and lesions were divided according to maximum axial diameter in more than 3 cm and 3 cm or less. The correlations between CT perfusion and PET/CT parameters were assessed in all tumors, as well as according to tumor diameter and volume.

Results

Lesion diameter and volume showed a negative correlation with BF and BV (r = −0.78, −0.78, −0.57, −0.48, respectively) and a positive correlation with mean transit time (r = 0.55, 0.65, respectively). The negative correlation between BF and lesion diameter and volume was confirmed in the subgroup of lesions of more than 3 cm (r = −0.68, −0.68, respectively). A positive correlation between SUVmax, SUVpeak, SUVmean, and lesion volume was observed (r = 0.50, 0.50, 0.46, respectively) and confirmed in lesions 3 cm or less (r = 0.81, 0.79, 0.78, respectively). Metabolic tumor volume and TLG showed a positive correlation with lesion diameter and volume in the overall population (r = 0.93, 0.87, 0.88, 0.90, respectively) and in lesions of more than 3 cm (r = 0.89, 0.84, 0.84, 0.79, respectively). Blood flow and BV showed a negative correlation with MTV and TLG (r = −0.77, −0.74, and −0.58, −0.48, respectively) in the overall population and with MTV in lesions of more than 3 cm (r = −0.69, −0.62, respectively).

Conclusions

Perfusion and metabolic parameters seem to depend on tumor size. The bigger the tumor, the lower the BF and the BV and, conversely, the higher the SUVpeak, MTV, and TLG. This information would be useful in the clinical setting when diagnosing or treating NSCLC, especially with novel therapies and/or for radiation treatment modulation.
Impact of Surgical Margin Width on Recurrence and Overall Survival Following R0 Hepatic Resection of Colorectal Metastases
Authors: Margonis Georgios A. , Sergentanis Theodoros N. , Ntanasis-Stathopoulos Ioannis , Andreatos Nikolaos , Tzanninis Ioannis-Georgios , Sasaki Kazunari , Psaltopoulou Theodora , Wang Jaeyun , Buettner Stefan , Papalois Αpostolos E. , He Jin , Wolfgang Christopher L. , Pawlik Timothy M. , Weiss Matthew J.
Published: November 2017

Objective:

To examine the impact of surgical margin width on survival following R0 hepatic resection for colorectal metastases (CRLM).

Summary of Background Data:

Although negative resection margin is considered of paramount importance for the prognosis of patients with colorectal liver metastases, optimal resection margin width remains controversial.

Methods:

Eligible studies examining the association between margin status after R0 hepatic resection for CRLM and survival, including overall survival (OS) and disease-free survival (DFS) were sought using the Medline, Cochrane, and EMBASE databases. Random-effects models were used for the calculation of pooled relative risks (RRs) with their 95% confidence intervals (95% CIs).

Results:

Thirty-four studies were deemed eligible for inclusion representing a cohort of 11,147 hepatic resections. Wider resection margin (>1 vs <1 cm) was significantly associated with improved OS at 3 years (pooled RR = 0.86, 95% CI: 0.79–0.95), 5 years (pooled RR = 0.91, 95% CI: 0.85–0.97), and 10 years (pooled RR = 0.94, 95% CI: 0.88–1.00). Similarly, DFS was positively associated with >1 cm resection margin at 3, 5, and 10 years. Interestingly, >1 mm (vs <1 mm) resection margin was significantly associated with improved OS at all-time points. Meta-regression analyses did not reveal any significant modifying role of the study features under investigation, such as the administration of neoadjuvant/adjuvant therapy.

Conclusions:

Importantly, our findings suggest that while a >1 mm margin is associated with better prognosis than a submillimeter margin, achieving a margin >1 cm may result in even better oncologic outcomes and should be considered if possible.
The Evolution of Surgical Strategies for Pancreatic Neuroendocrine Tumors (Pan-NENs)
Authors: Landoni Luca , Marchegiani Giovanni , Pollini Tommaso , Cingarlini Sara , D’Onofrio Mirko , Capelli Paola , De Robertis Riccardo , Davì Maria V. , Amodio Antonio , Impellizzeri Harmony , Malpaga Anna , Miotto Marco , Boninsegna Letizia , Crepaz Lorenzo , Nessi Chiara , Zingaretti Caterina C. , Paiella Salvatore , Esposito Alessandro , Casetti Luca , Malleo Giuseppe , Tuveri Massimiliano , Butturini Giovanni , Salvia Roberto , Scarpa Aldo , Falconi Massimo , Bassi Claudio
Published: November 2017

Objective:

The objective of the present analysis is 2-fold: first, to define the evolution of time trends on the surgical approach to pancreatic neuroendocrine neoplasms (Pan-NENs); second, to perform a complete analysis of the predictors of oncologic outcome.

Background:

Reflecting their rarity and heterogeneity, Pan-NENs represent a clinical dilemma. In particular, there is a scarcity of data regarding their long-term follow-up after surgical resection.

Methods:

From the Institutional Pan-NEN database, 587 resected cases from 1990 to 2015 were extracted. The time span was arbitrarily divided into 3 discrete clusters enabling a balanced comparison between patient groups. Analyses for predictors of recurrence and survival were performed, together with conditional survival analyses.

Results:

Among the 587 resected Pan-NENs, 75% were nonfunctioning tumors, and 5% were syndrome-associated tumors. The mean age was 54 years (±14 years), and 51% of the patients were female. The median tumor size was 20 mm (range 4 to 140), 62% were G1, 32% were G2, and 4% were G3 tumors. Time trends analysis revealed that the number of resected Pan-NENs constantly increased, while the size (from 25 to 20 mm) and G1 proportion (from 65% to 49%) decreased during the study period. After a mean follow-up of 75 months, recurrence analysis revealed that nonfunctioning tumors, tumor grade, N1 status, and vascular invasion were all independent predictors of recurrence. Regardless of size, G1 nonfunctioning tumors with no nodal involvement and vascular invasion had a negligible risk of recurrence at 5 years.

Conclusions:

Pan-NENs have been increasingly diagnosed and resected during the last 3 decades, revealing reliable predictors of outcome. Functioning and nodal status, tumor grade, and vascular invasion accurately predict survival and recurrence with resulting implications for patient follow-up.