bluuebunny/crossref_metadata_2025 huggingface dataset:
Utility of the Psychosocial Assessment of Candidates for Transplantation in Patients Undergoing Continuous-Flow Left Ventricular Assist Device Implantation
Authors: Halkar Meghana , Nowacki Amy S. , Kendall Kay , Efeovbokhan Nephertiti , Gorodeski Eiran Z. , Moazami Nader , Starling Randall C. , Young James B. , Lee Sangjin , Tang W.H. Wilson
Published: June 2018

Purpose:

Psychosocial assessment of patients comprises an important element in the selection process of appropriate candidates for left ventricular assist device (LVAD) implantation. We sought to determine the association of the well-validated psychosocial assessment of candidates for transplantation (PACT) scale to clinical outcomes post-LVAD implantation.

Materials and Methods:

The PACT scale was used retrospectively to reconstruct psychosocial profiles of all patients who underwent a continuous-flow LVAD implantation for all indications at our institution between March 2008 and August 2012 (N = 230). Psychosocial elements including social support, psychological health, lifestyle factors, comprehension of the operation, and follow-up were evaluated. The primary outcome was overall survival, and the secondary outcomes were hospital readmission, pump thrombosis, hemolysis, gastrointestinal (GI) bleeding, and LVAD driveline infections.

Results:

The mean age of patients was 55.3 years, with 83% being male; 58% (N = 135) were bridge to transplant and 42% (N = 95) were destination therapy. Up to 1-year post-LVAD implant, there were no statistical differences among the 5 PACT candidate groups in terms of survival ( P = .79), hospital readmissions ( P = .55), suspected or confirmed pump thrombosis ( P = .31), hemolysis ( P = .43), GI bleeding ( P = .71), or driveline infections ( P = .06).

Conclusions:

In this single-center retrospective review, post hoc reconstruction of psychosocial profiles using the PACT scale and independent assessment of postimplant outcomes, including survival and adverse events, did not show any association. However, given the small number of patients in the low score PACT groups as well as limited duration of follow-up, further studies are required to elucidate the association.
“If I Don’t Input Those Numbers . . . It Doesn’t Make Much of a Difference”: Insulated Precarity and Gendered Labor in Friends
Authors: Ewen Neil
Published: June 2018

This article examines the middle-class work culture of Friends, reading it as a text imbued with both Restorative and Reflective Nostalgia. I argue that the “insulated precarity” of Friends’ protagonists, and their seeming nonchalance about work, marks out the show as a prime example of a Clinton-era “boom” text and as a one that struggles with rising anxiety inherent in neoliberalism. I focus on the role of Chandler Bing, who quits his nondescript office job to follow his dreams, before realizing he does not know what they are, and ends up in advertising. I argue that while Friends’ self-reflexive comic mode facilitates sympathetic treatment of Chandler as a “New Man,” his perpetual crisis of masculinity (his infertility, his periodic reliance on his wife’s income, and the constant questioning of his sexuality) is related to the lack of purpose in his career and, thus, the changing work culture that characterized the period.
Adaptive compressive sensing of images using error between blocks
Authors: Li Ran , Duan Xiaomeng , Lv Yongfeng
Published: June 2018

Block compressive sensing of image results in blocking artifacts and blurs when reconstructing images. To solve this problem, we propose an adaptive block compressive sensing framework using error between blocks. First, we divide image into several non-overlapped blocks and compute the errors between each block and its adjacent blocks. Then, the error between blocks is used to measure the structure complexity of each block, and the measurement rate of each block is adaptively determined based on the distribution of these errors. Finally, we reconstruct each block using a linear model. Experimental results show that the proposed adaptive block compressive sensing system improves the qualities of reconstructed images from both subjective and objective points of view when compared with image block compressive sensing system.
Dehydrocorydaline attenuates bone cancer pain by shifting microglial M1/M2 polarization toward the M2 phenotype
Authors: Huo Wenwen , Zhang Ying , Liu Yue , Lei Yishan , Sun Rao , Zhang Wei , Huang Yulin , Mao Yanting , Wang Chenchen , Ma Zhengliang , Gu Xiaoping
Published: June 2018

Bone cancer pain remains a major challenge in patients with primary or metastatic bone cancer due to a lack of understanding the mechanisms. Previous studies have revealed the two distinct functional polarization states of microglia (classically activated M1 and alternatively activated M2) in the spinal cord in nerve injury–induced neuropathic pain. However, whether microglia in the spinal cord polarize to M1 and M2 phenotypes and contribute to the development of bone cancer pain remains unclear. In this study, we used a mouse model with bone cancer to characterize the M1/M2 polarization of microglia in the spinal cord during the development of bone cancer pain, and investigated the antinociceptive effects of dehydrocorydaline, an alkaloidal component isolated from Rhizoma corydalis on bone cancer pain. Our results show that microglia in the spinal cord presented increased M1 polarization and decreased M2 polarization, while overproduction of IL-1β and inhibited expression of IL-10 was detected during bone cancer pain development. Intraperitoneal administration of dehydrocorydaline (10 mg/kg) had significant antinociceptive effects on day 14 after osteosarcoma cell implantation, accompanied by suppressed M1 phenotype and upregulated M2 phenotype of microglia in the spinal cord, while alleviated inflammatory response was observed then. These results suggest that the imbalanced polarization of microglia toward the M1 phenotype in the spinal cord may contribute to the development of bone cancer pain, while dehydrocorydaline helps to attenuate bone cancer pain, with microglial polarization shifting toward the M2 phenotype in the spinal cord.
Morphophysiological Plasticity in Epiphytic Bromeliads Across a Precipitation Gradient in the Yucatan Peninsula, Mexico
Authors: Cach-Pérez Manuel Jesús , Andrade José Luis , Reyes-García Casandra
Published: June 2018

Plasticity may be a key factor to determine plant survival under a changing environment as a result of climate change or land use modification. Plasticity in physiological and morphological traits was evaluated in seven epiphytic Tillandsia species (Bromeliaceae) from six vegetation communities along a precipitation gradient in the Yucatan Peninsula, Mexico. Microenvironmental conditions (air temperature and humidity, light, and vapor pressure deficit), as well as Δ titratable acidity, osmotic potential, relative water content, and succulence were characterized during wet, early dry, and dry seasons. We calculated the relative distances plasticity index using physiological data from the wet and dry seasons; morphological plasticity was also calculated for foliar trichome and stomatal traits from previously published data. We found high variation in microenvironmental conditions between seasons, particularly for the tropical dry deciduous forest. The dry season had a negative effect in all physiological variables (decrease from 40% to 59% for Δ titratable acidity and 10% to 38% for relative water content). The highest plasticity was registered for T. balbisiana (physiological: 0.29, anatomical: 0.18) and the lowest for T. fasciculata and T. yucatana. Nonmetric multidimensional scaling analysis separated individuals distributed in the wettest vegetation types from those distributed in the driest vegetation types, irrespective of the species, showing convergent physiological strategies to confront environmental variation. We found higher plasticity in water use traits in atmospheric species, compared to tanks and higher plasticity in general in species with wide distribution compared to those with small distribution ranges.
Transverse venous sinus stenting for idiopathic intracranial hypertension: Safety and feasibility
Authors: Koovor Jerry ME , Lopez Gloria V , Riley Kalen , Tejada Juan
Published: June 2018

Purpose

Transverse sinus stenosis is commonly seen in patients with idiopathic intracranial hypertension. It is not clear whether it is the cause or the result of idiopathic intracranial hypertension. Stenting for idiopathic intracranial hypertension has been carried out in several prior series. Our goal was to evaluate the clinical and imaging follow-up results of patients with idiopathic intracranial hypertension that underwent stenting for this condition at our center.

Materials and Methods

We reviewed the clinical, venographic and follow-up imaging data in patients who underwent elective transverse sinus stenting during the period from 2011 to 2017.

Results

In total, 18 patients with idiopathic intracranial hypertension were identified. The mean lumbar cerebrospinal fluid opening pressure recorded was 408 mmH20. Overall, 16 patients met the inclusion criteria and underwent transverse sinus stenting. At venography, the mean pressure gradient across the dominant transverse sinus stenosis was 21 mmHg. The pressure gradient immediately after stenting in all of those measured was negligible. Following stenting, headaches improved in 10 of the 16 cases, with persistent headaches in four patients, one of which had persistent baseline migraines. All cases showed resolution of the papilledema on follow up. Follow-up imaging with computed tomography venography showed that the stents remained widely patent. The follow up in clinic was done for a mean period of 35.5 months. Follow up with computed tomography venography was done for a mean of 10.3 months.

Conclusion

Venous sinus stenting is a safe and effective procedure. It relieves papilledema in all cases and improves headaches in most cases.
Evaluating the use of high-fidelity simulators during mock neonatal resuscitation scenarios in trying to improve confidence in residents
Authors: Hossino Deena , Hensley Christina , Lewis Karen , Frazier Marie , Domanico Renee , Burley Melissa , Harris Jeffrey , Miller Bobby , Flesher Susan L
Published: June 2018

Objective:

The purpose of this study was to investigate the effect of the use of high-fidelity simulators with multidisciplinary teaching on self-reported confidence in residents.

Methods:

A total of 26 residents participated in a session led by a pediatric faculty member and a Neonatal Intensive Care Unit transport nurse using a high-fidelity pediatric simulator. Multiple scenarios were presented and each resident took turns in various roles. Pre-intervention surveys based on a 5-point Likert-type scale were given before the scenarios and were compared to the results of identical post-intervention surveys.

Results:

Statistically significant (p < 0.05) pre to post gains for self-confidence were observed. Improvements in confidence were analyzed using the mean difference. The largest improvement in confidence was seen in the ability to treat neonatal respiratory arrest. This was followed by the ability to supervise/run a code, and the ability to place an umbilical venous catheter.

Conclusion:

These results revealed that high-fidelity simulation-based training has significant positive gains in residents’ self-reported confidence.
My Foot: A Boutique with a Difference
Authors: Pai V.S. , Hiremath Chetan V.
Published: June 2018

My Foot was a boutique organization dealing with customized leather products and accessories. The CEO Manmath Shetty considered design, innovation, research & development and hand crafted products – keeping the basics as Indian originals- as core competency of his organization. He was keen to grow his business without losing focus on customization, the hallmark of his success. He intended to explore the possibilities of entering into adjacent spaces (product and customer) by replicating the existing business model. The option of moving from customized to volume customized products for a global market was also a tempting possibility to be explored.
Outcomes of Joint Preservation Procedures for Cartilage Injuries in the Hip: A Systematic Review and Meta-analysis
Authors: O’Connor Michaela , Minkara Anas A. , Westermann Robert W. , Rosneck James , Lynch T. Sean
Published: June 2018

Background:

The detection and management of chondral injuries of the hip, especially in a younger patient population, may preempt joint degeneration. Although the outcomes of preservation techniques have been well described for other weightbearing joints, such as the knee, evidence for hip joint preservation after procedures such as microfracture and autologous chondrocyte implantation remains in its infancy.

Purpose:

To evaluate outcomes of joint preservation procedures in the hip, including the success rate and patient-reported outcomes (PROs).

Study Design:

Systematic review; Level of evidence, 4.

Methods:

This review was performed using the terms “hip arthroscopy,” “microfracture,” “autologous chondrocyte implantation,” “fibrin glue,” “osteochondral transfer,” and variations thereof in 5 electronic databases, yielding 325 abstracts. After the application of eligibility criteria, 19 articles were included. Weighted means were calculated for PROs, and pooled estimates were calculated for age, follow-up, chondral lesion size, and success of hip preservation procedures with a random-effects proportion meta-analysis.

Results:

A total of 1484 patients (1502 hips) were identified across 19 studies (mean age, 38.0 ± 1.3 years; mean follow-up, 31.8 ± 9.6 months). Hip joint preservation techniques demonstrated a high success rate, ranging from 85.6% to 99.7%. The mean pooled chondral lesion size was 2.5 ± 0.3 cm2 (95% CI, 1.9-3.0 cm2). Microfracture was the most frequent technique, utilized by 11 studies, and demonstrated an 89.6% success rate (95% CI, 82.4%-96.7%). The highest pooled success rate was exhibited by autologous membrane-induced chondrogenesis in 3 studies (99.7% [95% CI, 99.0%-100.0%]). All PROs demonstrated a statistically significant increase postoperatively, including the modified Harris Hip Score, Nonarthritic Hip Score, and Hip Outcome Score–Activities of Daily Living and Hip Outcome Score–Sports-Specific Subscale (all P < .05). The visual analog scale for pain also demonstrated a statistically significant decrease of 37.2% ( P < .05).

Conclusion:

Hip preservation procedures demonstrate a high success rate, with microfracture representing the most frequently utilized cartilage preservation technique in the peer-reviewed literature. PROs significantly improved after surgery. Further investigation of hip preservation modalities with long-term follow-up is required to create evidence-based clinical recommendations and treatment algorithms.
A Comparison Between Subjective and Objective Methods of Predicting Health Care Expenses to Support Consumers’ Health Insurance Plan Choice
Authors: Politi Mary C. , Shacham Enbal , Barker Abigail R. , George Nerissa , Mir Nageen , Philpott Sydney , Liu Jingxia Esther , Peters Ellen
Published: June 2018

Objective. Numerous electronic tools help consumers select health insurance plans based on their estimated health care utilization. However, the best way to personalize these tools is unknown. The purpose of this study was to compare two common methods of personalizing health insurance plan displays: 1) quantitative healthcare utilization predictions using nationally representative Medical Expenditure Panel Survey (MEPS) data and 2) subjective-health status predictions. We also explored their relations to self-reported health care utilization. Methods. Secondary data analysis was conducted with responses from 327 adults under age 65 considering health insurance enrollment in the Affordable Care Act (ACA) marketplace. Participants were asked to report their subjective health, health conditions, and demographic information. MEPS data were used to estimate predicted annual expenditures based on age, gender, and reported health conditions. Self-reported health care utilization was obtained for 120 participants at a 1-year follow-up. Results. MEPS-based predictions and subjective-health status were related ( P < 0.0001). However, MEPS-predicted ranges within subjective-health categories were large. Subjective health was a less reliable predictor of expenses among older adults (age × subjective health, P = 0.04). Neither significantly related to subsequent self-reported health care utilization ( P = 0.18, P = 0.92, respectively). Conclusions. Because MEPS data are nationally representative, they may approximate utilization better than subjective health, particularly among older adults. However, approximating health care utilization is difficult, especially among newly insured. Findings have implications for health insurance decision support tools that personalize plan displays based on cost estimates.
Identification of novel mutational drivers reveals oncogene dependencies in multiple myeloma
Authors: Walker Brian A. , Mavrommatis Konstantinos , Wardell Christopher P. , Ashby T. Cody , Bauer Michael , Davies Faith E. , Rosenthal Adam , Wang Hongwei , Qu Pingping , Hoering Antje , Samur Mehmet , Towfic Fadi , Ortiz Maria , Flynt Erin , Yu Zhinuan , Yang Zhihong , Rozelle Dan , Obenauer John , Trotter Matthew , Auclair Daniel , Keats Jonathan , Bolli Niccolo , Fulciniti Mariateresa , Szalat Raphael , Moreau Philippe , Durie Brian , Stewart A. Keith , Goldschmidt Hartmut , Raab Marc S. , Einsele Hermann , Sonneveld Pieter , San Miguel Jesus , Lonial Sagar , Jackson Graham H. , Anderson Kenneth C. , Avet-Loiseau Herve , Munshi Nikhil , Thakurta Anjan , Morgan Gareth J.
Published: June 2018

Key Points

Using the largest set of patients with newly diagnosed myeloma, we identified 63 mutated driver genes. We identified oncogenic dependencies, particularly relating to primary translocations, indicating a nonrandom accumulation of genetic hits.
Whole genome sequencing reveals high clonal diversity of Escherichia coli isolated from patients in a tertiary care hospital in Moshi, Tanzania
Authors: Sonda Tolbert , Kumburu Happiness , van Zwetselaar Marco , Alifrangis Michael , Mmbaga Blandina T. , Aarestrup Frank M. , Kibiki Gibson , Lund Ole
Published: June 2018

Background

Limited information regarding the clonality of circulating E. coli strains in tertiary care hospitals in low and middle-income countries is available. The purpose of this study was to determine the serotypes, antimicrobial resistance and virulence genes. Further, we carried out a phylogenetic tree reconstruction to determine relatedness of E. coli isolated from patients in a tertiary care hospital in Tanzania.

Methods

E. coli isolates from inpatients admitted at Kilimanjaro Christian Medical Centre between August 2013 and August 2015 were fully genome-sequenced at KCMC hospital. Sequence analysis was done for identification of resistance genes, Multi-Locus Sequence Typing, serotyping, and virulence genes. Phylogeny reconstruction using CSI Phylogeny was done to ascertain E. coli relatedness. Stata 13 (College Station, Texas 77,845 USA) was used to determine Cohen’s kappa coefficient of agreement between the phenotypically tested and whole genome sequence predicted antimicrobial resistance.

Results

Out of 38 E. coli isolates, 21 different sequence types (ST) were observed. Eight (21.1%) isolates belonged to ST131; of which 7 (87.5.%) were serotype O25:H4. Ten (18.4%) isolates belonged to ST10 clonal complex; of these, four (40.0%) were ST617 with serotype O89:H10. Twenty-eight (73.7%) isolates carried genes encoding beta-lactam resistance enzymes. On average, agreement across all drugs tested was 83.9%. Trimethoprim/sulphamethoxazole (co-trimoxazole) showed moderate agreement: 45.8%, kappa =15% and p = 0.08. Amoxicillin-clavulanate showed strongest agreement: 87.5%, kappa = 74% and p = 0.0001. Twenty-two (57.9%) isolates carried virulence factors for host cells adherence and 25 (65.7%) for factors that promote E. coli immune evasion by increasing survival in serum. The phylogeny analysis showed that ST131 clustering close together whereas ST10 clonal complex had a very clear segregation of the ST617 and a mix of the rest STs.

Conclusion

There is a high diversity of E. coli isolated from patients admitted to a tertiary care hospital in Tanzania. This underscores the necessity to routinely screen all bacterial isolates of clinical importance in tertiary health care facilities. WGS use for laboratory-based surveillance can be an effective early warning system for emerging pathogens and resistance mechanisms in LMICs.
Monitoring the changes in the microstructure and the elastic and transport properties of Eagle Ford marl during maturation
Authors: Suwannasri Krongrath , Vanorio Tiziana , Clark Anthony
Published: June 2018

Organic-rich marl is one of the best unconventional reservoirs because of its high calcite and low clay content leading to relatively high permeability and fracability. However, how its stiff pores and relatively high permeability affect the changes in its microstructure and elastic and transport properties during maturation remains a research interest. We have induced ex situ maturation of organic-rich marl core plugs by conducting confined pyrolysis in fine steps across the maturity windows from immature through the early-peak oil, late oil, wet gas, and finally, the dry gas window. This was performed under high and low confining pressures on different samples to investigate the role of confining pressure during maturation. After each pyrolysis, we monitored the changes in microstructure, porosity, velocity, permeability, and geochemical properties. The results indicate increasing porosity, decreasing velocity, and increasing permeability as the maturation progresses. The time-lapse scanning electron microcopy images reveal the progressive development of secondary organic porosity at the expense of kerogen volume. Most of the changes in the acoustic velocity and permeability occur in the late oil window and are concurrent with the generation of connected secondary organic porosity. The total organic carbon (TOC) and Rock-Eval results indicate that most of the generated hydrocarbons immediately exit the samples during pyrolysis so that the generation of microcracks from pore-pressure buildup is unlikely. Rather, secondary organic porosity is the main microstructural change, and the amount of depleted TOC can be used as a proxy to predict the increase in porosity and the changes in the velocity and permeability. Finally, confining pressure plays a minor role in the evolution of the elastic and transport properties of organic-rich marl.
Estimating permeability of shale-gas reservoirs from porosity and rock compositions
Authors: Zhao Peiqiang , Cai Jianchao , Huang Zhenhua , Ostadhassan Mehdi , Ran Fuqiang
Published: June 2018

Effectively estimating the permeability of shale-gas reservoirs by traditional models is challenging; however, study in this area is lacking and deficient. We have developed a method for predicting the permeability of shale-gas reservoirs from porosity and rock compositions including mineralogy and organic matter content, which is applicable to laboratory data and downhole measurements. First, two sets including 38 samples from the Longmaxi Formations were tested for porosity, permeability, grain density, total-organic-carbon (TOC) content, mineralogical composition, and low-temperature nitrogen adsorption (LTNA). We used Kozeny’s equation to calculate the specific surface area, which was viewed as the effective specific surface in shale formations through comparing with the specific surface from LTNA. Furthermore, the effective specific surface was found to be positively correlated with clays, pyrite, and TOC contents, whereas it was negatively correlated with quartz, feldspar, and carbonates. Then, an empirical equation between the effective specific surface area and rock compositions was established via a partial least-squares method, which can process the serious multicollinearity of various mineral contents. Combined with Kozeny’s equation, this equation enabled a prediction of permeability from porosity and rock composition. The results indicated that the predicted and measured permeability have a reasonable match. Compared with other models, this method avoids the correlations between porosity and minerals, providing better insight to the influence of minerals and organic matter on permeability. The influences of rock composition on permeability are different, and are caused by the different types and sizes of pores developed within the minerals and organic matter. In addition, the new method was successfully applied to the well-log data from a shale-gas well for permeability predictions.
Results of downhole microseismic monitoring at a pilot hydraulic fracturing site in Poland — Part 2: S-wave splitting analysis
Authors: Gajek Wojciech , Malinowski Michał , Verdon James P.
Published: June 2018

Observations of azimuthal seismic anisotropy provide useful information, notably on stress orientation and the presence of preexisting natural fracture systems, during hydraulic fracturing operations. Seismic anisotropy can be observed through the measurement of S-wave splitting (SWS) on waveforms generated by microseismic events and recorded on downhole geophone arrays. We have developed measurements of azimuthal anisotropy from a Lower Paleozoic shale play in northern Poland. The observed orthorhombic anisotropic symmetry system is dominated by a vertically transverse isotropy (VTI) fabric, produced by the alignment of anisotropic platy clay minerals and by thin horizontal layering and overprinted by a weak azimuthal anisotropy. Despite the dominating VTI fabric, we successfully identified a weaker horizontal-transverse isotropy fabric striking east–southeast. We do this by constraining the rock-physics model inversion with VTI background parameters incorporated from other geophysical methods: microseismic velocity model inversion, 3D reflection seismic, and borehole cross-dipole sonic logs. The obtained orientation is consistent with a preexisting natural fracture set that has been observed using X-ray micro-imaging (XRMI) image logs from a nearby vertical well. The present-day regional maximum horizontal stress direction differs from the observed fracture strike by approximately 45°. This implies that the SWS measurements recorded during hydraulic stimulation of a shale-gas reservoir are imaging the preexisting natural fracture set, which influences the treatment efficiency, instead of the present-day stress.
Gastrointestinal and Hepatic Toxicities of Checkpoint Inhibitors: Algorithms for Management
Authors: Grover Shilpa , Rahma Osama E. , Hashemi Nikroo , Lim Ramona M.
Published: June 2018

Gastrointestinal toxicities are among the leading causes of immune-related adverse effects of checkpoint blockade. These adverse events can be severe enough to require interruption or withdrawal of immune checkpoint blockade therapy. Patients with immune-related adverse effects require early recognition with an evaluation to rule out alternative etiologies and effective management to minimize complications. This article reviews the gastrointestinal and hepatic toxicities of the antibodies that target immune checkpoints CTLA-4 and PD-1/PD-L1 and provides an approach to their diagnosis and management.
Predicting and Preventing Anthracycline-Related Cardiotoxicity
Authors: Armenian Saro , Bhatia Smita
Published: June 2018

Anthracyclines (doxorubicin, daunorubicin, epirubicin, and idarubicin) are among the most potent chemotherapeutic agents and have truly revolutionized the management of childhood cancer. They form the backbone of chemotherapy regimens used to treat childhood acute lymphoblastic leukemia, acute myeloid leukemia, Hodgkin lymphoma, Ewing sarcoma, osteosarcoma, and neuroblastoma. More than 50% of children with cancer are treated with anthracyclines. The clinical utility of anthracyclines is compromised by dose-dependent cardiotoxicity, manifesting initially as asymptomatic cardiac dysfunction and evolving irreversibly to congestive heart failure. Childhood cancer survivors are at a five- to 15-fold increased risk for congestive heart failure compared with the general population. Once diagnosed with congestive heart failure, the 5-year survival rate is less than 50%. Prediction models have been developed for childhood cancer survivors (i.e., after exposure to anthracyclines) to identify those at increased risk for cardiotoxicity. Studies are currently under way to test risk-reducing strategies. There remains a critical need to identify patients with childhood cancer at diagnosis (i.e., prior to anthracycline exposure) such that noncardiotoxic therapies can be contemplated.
Incorporating Immunotherapy Into the Treatment Strategies of B-Cell Adult Acute Lymphoblastic Leukemia: The Role of Blinatumomab and Inotuzumab Ozogamicin
Authors: Kantarjian Hagop , Jabbour Elias
Published: June 2018

Monoclonal antibodies and bispecific antibody constructs hold considerable promise in improving the outcomes of patients with acute lymphoblastic leukemia (ALL). Antibody-drug conjugates such as inotuzumab ozogamicin and the bispecific T-cell engager blinatumomab represent novel antibody constructs that have shown substantial clinical activity in ALL. Although most studies have focused on the use of these agents in the salvage setting, incorporation of these antibodies into the frontline regimens is imperative to improve long-term survival for patients with ALL and to increase the cure rates of adult ALL to the levels achieved in the pediatric population.
Liquid Biopsy to Identify Actionable Genomic Alterations
Authors: Ou Sai-Hong Ignatius , Nagasaka Misako , Zhu Viola W.
Published: June 2018

Liquid biopsy has been used extensively in solid malignancies to detect actionable driver mutations, to monitor treatment response, to detect recurrence, to identify resistance mechanisms, and to prognosticate outcome. Although many liquid biopsy sequencing platforms are being used, only five test kits have received government approval. We review representative literature on these government-approved liquid biopsy kits, which are primarily used to detect EGFR mutation in lung cancer and RAS ( KRAS, NRAS, BRAF) mutations in colorectal carcinoma. Another emerging use of single-gene liquid biopsy is to detect PIK3CA mutations and to understand resistance to hormonal blockade in breast and prostate cancers. The two most commonly used next-generation sequencing (NGS) liquid biopsy tests (Guardant 360, Guardant Health; FoundationACT, Foundation Medicine Inc.) are discussed. The ability and the applicability of NGS platform to detect tumor mutation burden are also addressed. Finally, the use of circulating tumor DNA (ctDNA) to detect minimal residual disease may be the most important use of ctDNA in the setting of tumor heterogeneity. The ability to identify “shedders” and “nonshedders” of ctDNA may provide important insight into the clinicopathologic characteristics of the tumor and portend important prognostic significance regarding survival.
Next-Generation Novel Noninvasive Cancer Molecular Diagnostics Platforms Beyond Tissues
Authors: Wu Xiaoliang , Zhu Lin , Ma Patrick C.
Published: June 2018

In recent years, there has been a revolutionary expansion in technologic advances and therapeutic innovations in cancer medicine. Cancer diagnostics has begun to move away from a sole dependence on direct tumor tissue biopsy for cancer detection, diagnosis, and treatment monitoring. The need for improvement in molecular cancer diagnostics has never been more important, with not only the advent of cancer genomics and genomics-guided precision medicine but also the recent arrival of cancer immunotherapies. Owing to the practical limitations and risks associated with tissue-based biopsy diagnostics, novel noninvasive cancer diagnostics platforms have continued to evolve and expand in recent years. Examples of these platforms include the liquid biopsy, which is used to interrogate ctDNA or circulating tumor cells, proteomics, metabolomics, and exosomes; the urine biopsy, which is used to assay ctDNAs; saliva and stool biopsies, which are used for molecular genomics assays; and the breath biopsy, which measures volatile organic compounds. These next-generation noninvasive molecular diagnostics assays beyond tissues fundamentally transform the potential utilities of cancer diagnostics to enable repeat, prospective, and serial longitudinal “biopsies” to monitor disease response resistance and progression on therapies. Moreover, they allow continual interrogation and molecular in-depth analysis of the evolving tumor’s pan-canceromics under therapeutic stress. These technological and diagnostic advances have already brought about paradigm-changing next-generation cancer therapeutic strategies to enhance overall treatment efficacies. This article reviews the key noninvasive next-generation molecular diagnostics platforms beyond tissues, with emphasis on clinical utilities and applications.
National Cancer Institute Programmatic Collaboration for Investigational Radiopharmaceuticals
Authors: Kunos Charles A. , Capala Jacek
Published: June 2018

Radiopharmaceutical therapies have provided an attractive therapeutic approach since the introduction of 131I to treat thyroid cancer. New insights in cancer biology and radiochemistry have brought radiopharmaceuticals to the leading edge of oncology clinical research. National Cancer Institute (NCI) programs watch for new radiopharmaceutical breakthroughs that should be used to treat patients with unmet therapeutic needs. Such efforts occur through leveraged partnerships between NCI’s Cancer Therapy Evaluation Program and its Radiation Research Program. If groundbreaking discoveries are made, NCI pulls together clinician scientists to design novel radiopharmaceutical phase I and II monotherapy or combination trials. The specific infrastructure needs, such as radiopharmaceutical dosimetry and treatment planning, demand new programmatic workflow and regulatory oversight. This article discusses a modern approach to the development of radiopharmaceutical therapies in the era of personalized medicine.
Management of Biochemically Recurrent Prostate Cancer: Ensuring the Right Treatment of the Right Patient at the Right Time
Authors: Spratt Daniel E. , McHugh Deaglan J. , Morris Michael J. , Morgans Alicia K.
Published: June 2018

Biochemically recurrent prostate cancer is an increasingly common disease state, with more than 25,000 cases occurring annually in the United States. Fortunately, progress continues to be made to more effectively identify metastatic disease, optimize existing therapies, and develop new technologies and therapeutic strategies for the timing and delivery of systemic treatments to improve outcomes. This review covers three topics related to the diagnosis and treatment of men with biochemical recurrence (BCR). First, we provide an update on the state of the rapidly evolving field of molecular imaging and its place in practice. Second, we describe validated clinicopathologic methods to risk stratify patients with biochemically recurrent disease, including new gene expression classifiers, to personalize postoperative radiotherapy (RT) timing. Last, we define our approach to optimal management with systemic therapy, including identifying the patients who may benefit most and balancing the duration and timing of treatment with consideration of the effect of therapy on quality of life (QOL) and medical complications associated with treatment.
Cost, Value, and Financial Hardship in Cancer Care: Implications for Pediatric Oncology
Authors: Parsons Susan K. , Castellino Sharon M. , Yabroff K. Robin
Published: June 2018

Cancer care in the United States faces a perfect storm: an aging population and expected increased cancer incidence, growing numbers of cancer survivors with ongoing care needs, and continued scientific advancements, offering extraordinary promise at extraordinary cost. How, then, do we as pediatric oncologists engage in the dialogue about cancer cost considerations? The purpose of this article and its accompanying session presented at the 2018 ASCO Annual Meeting is to introduce concepts of cost, value, and financial hardship. In the first section, we will provide an overview of principles of health economics, including components of cost, time horizon consideration, discounting, and methods to calculate incremental cost-effectiveness among therapeutic approaches. We will then introduce the value framework being debated in adult oncology and offer potential opportunities for its application in pediatric oncology. In the second section, we will describe the integration of the cost-effectiveness paradigm in an ongoing pediatric clinical trial, including design and analytic considerations. In the third section, we will shift away from cost to the health care system to cost to the patient, which is also termed “financial toxicity” or “financial hardship,” focusing on the ongoing burden of cost on survivors of childhood cancer. Our goal is to provide our readers with the vocabulary and understanding of this complex and often thorny debate so that they can be active participants and informed advocates for their patients.
Innovative Strategies: Targeting Subtypes in Metastatic Breast Cancer
Authors: Pegram Mark D. , Zong Yu , Yam Clinton , Goetz Matthew P. , Moulder Stacy L.
Published: June 2018

Metastatic breast cancer continues to be a life-threatening diagnosis that impacts hundreds of thousands of patients around the world. Targeted therapies are usually associated with less toxicity compared with cytotoxic chemotherapies and often induce response or durable disease control in estrogen receptor (ER) and/or HER2+ breast cancers. Drugs that target CDK 4/6 either alone or in combination with endocrine therapy have demonstrated substantial improvements in progression-free survival (PFS) compared with endocrine monotherapy. Most recently, PARP inhibitors have shown longer PFS compared with physician’s choice of chemotherapy in BRCA-associated cancers, leading to the first U.S. Food and Drug Administration (FDA) approval of a targeted therapy with the potential to benefit a subgroup of patients with triple-negative breast cancer (TNBC). Finally, newer drug delivery strategies using antibody drug conjugates have also allowed a “targeted approach” to deliver moderate to extremely potent cytotoxins directly to sites of metastatic disease, with less toxicity.
Is There a Precise Adjuvant Therapy for Esophagogastric Carcinoma?
Authors: Cartwright Elizabeth , Keane Florence K. , Enzinger Peter C. , Hong Theodore , Chau Ian
Published: June 2018

Esophagogastric cancer remains a leading cause of cancer-related mortality worldwide. The prognosis for patients with locally advanced disease is poor and the majority of patients with operable tumors treated with surgery alone will have recurrent disease. A multimodal approach to treatment with adjunctive chemotherapy or chemoradiotherapy is therefore the standard of care for these patients. However, there is no global consensus on the optimal treatment strategy and international guidelines vary. National clinical trials inform local practice: neoadjuvant, perioperative, and adjuvant chemotherapy and radiotherapy combinations are all possible treatment options in the management of resectable esophagogastric cancer. A number of clinical trials are ongoing, which seek to directly compare multimodal treatment options and hope to provide clarity in this area. Furthermore, increased understanding of the molecular and genetic features of esophagogastric cancer may help to guide management of operable disease by determining optimal patient selection through identification of predictive biomarkers of response and the application of novel targeted agents.
New Era in the Management of Melanoma Brain Metastases
Authors: Tawbi Hussein A. , Boutros Celine , Kok David , Robert Caroline , McArthur Grant
Published: June 2018

The remarkable advances in the systemic therapy of metastatic melanoma have now extended the 1-year overall survival rate from 25% to nearing 85%. Systemic treatment in the form of BRAF-targeted therapy and immunotherapy is slowly but surely proving its efficacy in the treatment of metatstatic brain metastases (MBM). Single-agent BRAF inhibitors provide an intracranial response rate of 25% to 40%, whereas the combination of BRAFi/MEKi leads to responses in up to 58%. However, the durability of responses induced by BRAFi/MEKi seems to be even shorter than in extracranial disease. On the other hand, single-agent ipilimumab provides comparable clinical benefit in MBMs as it does in extracranial metastases. Single-agent PD-1 anitbodies induce response rates of approximately 20%, and those responses appear durable. Similarly the combination of CTLA-4+ PD-1 antibodies induces durable responses at an impressive rate of 55% and is safe to administer. Although the local treatment approaches with radiation and surgery remain important and are critically needed in the management of MBM, systemic therapy offers a new dimension that can augment the impact of those therapies and come at a potentially lower cost of neurocognitive impairment. Considerations for combining those modalities are direly needed, in addition to considering novel systemic combinations that target mechanisms specific to MBM. In this report, we will discuss the underlying biology of melanoma brain metastases, the clinical outcomes from recent clinical trials of targeted and immunotherapy, and their impact on clinical practice in the context of existing local therapeutic modalities.
What Makes a Pancreatic Cancer Resectable?
Authors: Evans Douglas B.
Published: June 2018

The majority of patients with localized pancreatic cancer who undergo surgery with or without adjuvant therapy will develop metastatic disease, suggesting that surgery alone is not sufficient for cure and micrometastases are present at the time of diagnosis even when not clinically apparent. As such, the field is rapidly moving to consensus on treatment sequencing, which emphasizes the early delivery of systemic therapy and the application of surgery to the population of patients most likely to receive clinical benefit from such large operations—namely, those with stable or responding disease following systemic therapy and often chemoradiation. There remains incomplete consensus about the definition of what is operable (both tumor anatomy and patient age/comorbidities) and whether the operation should be performed in a high-volume center by more experienced surgeons. In this article, we try to provide a comprehensive description of when surgery should be performed and what constitutes an operable tumor. Such information is critically important for the optimal delivery of stage-specific therapy and to allow physicians to provide accurate expectations to all patients for treatment outcome. The complex issues of where and by whom such large operations should be performed is beyond the scope of this review.
Risk Stratification and Targets in Multiple Myeloma: From Genomics to the Bedside
Authors: Perrot Aurore , Corre Jill , Avet-Loiseau Hervé
Published: June 2018

In the past 15 years, significant improvements in overall survival have been observed in multiple myeloma (MM), mainly due to the availability of novel drugs with variable mechanisms of action. However, these improvements do not benefit all patients, and some of them, defined as high risk, still display short survival. The most important risk factors are the genetic abnormalities present in the malignant plasma cells. The most important high-risk features are the del(17p), the del(1p32), the t(4;14), and 1q gains. Assessing these markers is mandatory at diagnosis and at least at first relapse, since it has been clearly shown that the lenalidomide-dexamethasone combination is not efficient in these high-risk patients. In contrast, a triplet combination adding a proteasome inhibitor or a monoclonal antibody to the lenalidomide-dexamethasone backbone clearly improves the survival. Another way to improve the outcome would be to specifically target genetic abnormalities with specific inhibitors. The sequencing of more than 1,000 MM exomes revealed again a huge heterogeneity. The most frequent mutations involve the KRAS and NRAS genes (20%–25% each). However, to date, no good RAS-inhibitors are clinically available, preventing targeted therapy. The only drugable target is the V600E BRAF mutation. Unfortunately, this specific mutation is present in only 3% of the patients. Finally, it has been recently reported a specific efficiency of the BCL2-inhibitor venetoclax in patients with the t(11;14) translocation, which is found in 20% of the patients.
Understanding Utilization Management Policy: How to Manage This Increasingly Complex Environment in Collaboration and With Better Data
Authors: Patt Debra A.
Published: June 2018

As innovation in cancer care continues and newer costly therapies receive approval, utilization management will continue to grow as an important way that payers can attempt to control costs and value while providing service to their patients. Although utilization management may be necessary, it takes many forms and is optimized when it ensures appropriate patient access to services and minimizes administrative burdens of physicians and staff. These opportunities are best explored in collaboration with payers. Information systems today provide an excellent platform for data sharing to facilitate collaborative efforts between care delivery organizations and payers to optimize these efforts. As state and national policies differ regarding utilization management, it is important for clinicians to be both aware and involved.
Global Epidemiology, Prevention, and Management of Hepatocellular Carcinoma
Authors: Mak Lung-Yi , Cruz-Ramón Vania , Chinchilla-López Paulina , Torres Harrys A. , LoConte Noelle K. , Rice John P. , Foxhall Lewis E. , Sturgis Erich M. , Merrill Janette K. , Bailey Howard H. , Méndez-Sánchez Nahum , Yuen Man-Fung , Hwang Jessica P.
Published: June 2018

The incidence rate of hepatocellular carcinoma (HCC) is rising. It is one of the most common cancers worldwide and accounts for substantial morbidity and mortality. Chronic hepatitis B virus (HBV) infection, chronic hepatitis C virus (HCV) infection, and nonalcoholic fatty liver disease (NAFLD) are the most important etiologies of HCC, and effective screening and management strategies are crucial to reduce the HCC risk. For HBV, which accounts for the majority of HCC cases, most infections were acquired via perinatal and early horizontal transmission. Universal vaccination of newborns has led to a decline in HCC incidence compared with the pre-vaccination era. Effective antiviral therapies with nucleos(t)ide analogues or pegylated interferon reduced the incidence of HCC. For HCV, the emergence of effective direct-acting antiviral (DAA) agents has substantially improved cure rates; therefore all patients with HCV should be considered for DAA treatment. The most important obstacle in eliminating HCV is access to therapy. For NAFLD, the global incidence is increasing rapidly, thus its impact on HCC incidence may be explosive. Progression to HCC in NAFLD happens particularly in those with nonalcoholic steatohepatitis (NASH) and exacerbated by metabolic syndrome, or PNPLA3 gene polymorphism. Lifestyle changes are imperative while drug therapy has yet to demonstrate substantive protective effects on HCC prevention. For management of HCC, early diagnosis via imaging surveillance among persons with HCC risk factors remains the most important strategy to identify early-stage disease appropriate for resection or transplantation.