bluuebunny/crossref_metadata_2025 huggingface dataset:
Salutary Response to Targeted Therapy in Anaplastic Thyroid Cancer
Authors: Fazeli Sasan , Paal Edina , Maxwell Jessica H. , Burman Kenneth D. , Nylen Eric S. , Khosla Shikha G.
Published: November 2019

Context. Anaplastic thyroid cancer (ATC) is an aggressive tumor with a median survival of 3 to 9 months, a 1-year survival of less than 10% and without definitive therapies. Recently, in BRAF V600E mutated ATCs, new targeted therapy using a combination of a BRAF inhibitor, dabrafenib (Dab), with a mitogen-activated extracellular protein kinase (MEK) inhibitor, trametinib (Tram), has shown significant promise. Case Description. We report a case of aggressive ATC with 5 sequence mutations: BRAF V600E (mutation fraction [MF] 34%), TERT E441del (MF 37%), RET N579K (MF 55%), EZH2 D154E (MF 60%), and CDK4 S259L (MF 48%). The patient had a dramatic response to the Dab/Tram combination with near complete resolution of his lung, bone, hepatic, and splenic lesions soon after starting therapy. Unfortunately, intolerable side effects (grade 2-3) on this regimen required tapering and discontinuation of the treatment. He had a quick resurgence of disease after stopping the combination therapy. The patient died approximately 3 months after discontinuing Dab/Tram. Autopsy revealed an atrophic thyroid gland with microscopic subcapsular focus of well-differentiated papillary thyroid carcinoma. There was extensive lymphatic spread of the tumor throughout bilateral lungs with fibrosis. No other metastatic site was identified. Conclusion. We report a unique case of ATC with 2 new mutations of EZH2 D154E and CDK S529L. This case exemplifies the significant promise Dab/Tram therapy holds, the potential side effects that limit their use, and autopsy findings status post use of this combination therapy.
BST-236, a novel cytarabine prodrug for patients with acute leukemia unfit for standard induction: a phase 1/2a study
Authors: Zuckerman Tsila , Ram Ron , Akria Luiza , Koren-Michowitz Maya , Hoffman Ron , Henig Israel , Lavi Noa , Ofran Yishai , Horowitz Netanel A. , Nudelman Olga , Tavor Sigal , Yeganeh Shay , Gengrinovitch Stela , Flaishon Liat , Tessler Shoshi , Ben Yakar Ruth , Rowe Jacob M.
Published: November 2019

Key Points

The majority of older adults or unfit acute leukemia patients are not offered intensive therapy, resulting in dismal long-term survival. A novel cytarabine prodrug BST-236 enables delivery of high-dose cytarabine and appears to be safe and efficacious in these patients.
Facilitating equitable community-level access to maternal health services: exploring the experiences of Rwanda’s community health workers
Authors: Tuyisenge Germaine , Crooks Valorie A. , Berry Nicole S.
Published: November 2019

Background

In Rwanda, community health workers (CHWs) are an integral part of the health system. For maternal health, CHWs are involved in linking members of the communities in which they live to the formal health care system to address preventative, routine, and acute maternal care needs. Drawing on the findings from in-depth interviews with maternal health CHWs and observational insights in ten Rwandan districts, we identify specific strategies CHWs employ to provide equitable maternal care while operating in a low resource setting.

Methods

Using case study methodology approach, we conducted interviews with 22 maternal health CHWs to understand the nature of their roles in facilitating equitable access to maternal care in Rwanda at the community level. Interviews were conducted in five Rwandan districts. Participants shared their experiences of and perceptions on promoting equitable access to maternal health service in their communities.

Results

Four key themes emerged during the analytic process that characterize the contexts and strategic ways in which maternal health CHWs facilitate equitable access to maternal care in an environment of resource scarcity. They are: 1) community building; 2) physical landscapes, which serve as barriers or facilitators both to women’s care access and CHWs’ equitable service provision; 3) the post-crisis socio-political environment in Rwanda, which highlights resilience and the need to promote maternal health subsequent to the genocide of 1994; and, 4) the strategies used by CHWs to circumvent the constraints of a resource-poor setting and provide equitable maternal health services at the community level.

Conclusion

Rwanda’s maternal CHWs are heavily responsible for promoting equitable access to maternal health services. Consequently, they may be required to use their own resources for their practice, which could jeopardize their own socio-economic welfare and capacity to meet the demands of their families. Considering the unpaid and untrained nature of this position, we highlight the factors that threaten the sustainability of CHWs’ role to facilitate equitable access to maternal care. These threats introduce turbulence into what is a relatively successful community-level health care initiative.
Effect of apparent temperature on daily emergency admissions for mental and behavioral disorders in Yancheng, China: a time-series study
Authors: Min Min , Shi Tingting , Ye Pengpeng , Wang Yuan , Yao Zhenhai , Tian Shun , Zhang Yun , Liang Mingming , Qu Guangbo , Bi Peng , Duan Leilei , Sun Yehuan
Published: November 2019

Background

Very few studies have focused on the relationship between ambient apparent temperature (AT) and admission of mental and behaviour disorders (MDs). Therefore, a time-series study was conducted in Yancheng, China, to explore the effects of AT on the daily emergency admissions of patients with MDs over the period of 2014–17.

Methods

A quasi-Poisson generalized linear model (GLM) combined with a distributed lag non-linear model (DLNM) was adopted to explore the associations after adjusting for time trend, day of the week, humidity, sunshine duration, rainfall, holidays and air pollutants. In the subgroup analysis, the modification effects of age and sex were also examined.

Results

Overall, 8438 cases of MDs emergency admissions were identified. With the apparent temperature with the minimum number of admissions (− 3.4 °C) serving as a reference, a positive correlation emerged between high AT and daily emergency admissions of patients with MDs in Yancheng, China, with the lagged effect of 1 to 5 days. The subgroup analysis demonstrated a positive relationship between AT and MDs emergency admissions among males and individuals younger than 45 years old, with no lagged effect.

Conclusions

The results will provide important scientific evidence for mental health policy-makers and practitioners for possible intervention, especially among the vulnerable populations.
Assessing the contribution of harvested wood products under greenhouse gas estimation: accounting under the Paris Agreement and the potential for double-counting among the choice of approaches
Authors: Sato Atsushi , Nojiri Yukihiro
Published: November 2019

Background

There are multiple approaches for estimating emissions and removals arising from harvested wood products (HWP) based on differences between when and where a given carbon stock change is calculated. At this moment, countries are free to use any HWP approach to prepare their annual greenhouse gas (GHG) inventory and determine emission reduction targets for their Nationally Determined Contributions (NDCs), although under the Paris Agreement (PA), the production approach is used for standard reporting in GHG inventories. Global double-counting and non-counting of HWP might occur depending on the HWP approach each country uses; however, the impact of such double-counting and non-counting has not been thoroughly evaluated.

Results

We identified all cases of global double-counting and non-counting of HWP for combinations of the six HWP approaches: ‘instantaneous oxidation’, ‘stock-change’, ‘production’, ‘stock-changes approach for HWP of domestic origin (SCAD)’, ‘simple-decay’ and ‘atmospheric-flow’ approaches. In Intended Nationally Determined Contributions (INDCs), forest land is often partly or completely excluded, especially by developing countries. In such cases, HWP approaches that require comprehensive national data on wood harvesting and trade are not suitable for estimating HWP contributions. In addition, most developing countries apply the ‘instantaneous oxidation’ at the time of harvesting. Recent GHG inventories from Annex I countries show the averaged contribution of annual HWP emissions or removals to national total emissions is nearly 1%; therefore, the potential contribution of HWP to the accounted emission reduction volume is assumed to be a smaller value.

Conclusions

Instantaneous oxidation remains a pragmatic approach for countries in which wood production is not a dominant part of the economy. The combination of ‘instantaneous oxidation’ with the ‘production’, ‘SCAD’ or ‘simple-decay’ approaches could be a practical solution to realize a global HWP accounting approach the eliminates double-counting. Regardless of how global double-counting and non-counting occur, the amount is not large. To improve the accuracy of the global assessment, it is important to reduce the uncertainty of estimation regarding when and how much HWP-related emissions occur at national level.
Serum metabolite markers of early Mycoplasma hyopneumoniae infection in pigs
Authors: Surendran Nair Meera , Yao Dan , Chen Chi , Pieters Maria
Published: November 2019

Mycoplasma hyopneumoniae, the primary pathogenic bacterium causing enzootic pneumonia, significantly affects worldwide swine production. The infection is usually persistent and bacterial identification and isolation of M. hyopneumoniae in clinical samples are challenging due to the fastidious requirements for its growth. Hence, new practical surveillance tools that improve or complement existing diagnostics on M. hyopneumoniae are desirable, especially in early infection. The objective of this study was to identify potential metabolite markers of early M. hyopneumoniae infection in pigs through metabolomics analysis. Samples obtained from pigs in a previous M. hyopneumoniae experimental infection were used in this study. Briefly, two pigs served as mock inoculated controls and ten pigs were intra-tracheally inoculated with M. hyopneumoniae. Sera, laryngeal swabs (LS), and tracheo-bronchial lavage fluid (TBLF) were collected from all pigs at 0, 2, 5, 9, 14, 21 and 28 days post-inoculation (dpi). Bronchial swabs (BS) were collected post-mortem at 28 dpi. Mycoplasma hyopneumoniae infection was confirmed by PCR in LS, TBLF and BS. Serum metabolites were profiled using high-resolution liquid chromatography–mass spectrometry (LC–MS) analysis. Metabolite markers were identified by structural analysis following multivariate analysis of LC–MS data. The results showed that M. hyopneumoniae infection time-dependently altered the serum levels of selective amino acids and fatty acids. α-Aminobutyric acid and long-chain fatty acids were markedly increased at 14 and 21 dpi in inoculated pigs (p < 0.05). These results indicated that M. hyopneumoniae infection caused systemic changes in host metabolism, warranting further studies to determine underlying biochemical and physiological mechanisms responsible for the observed changes.
Limit theorems for ratios of order statistics from uniform distributions
Authors: Xu Shoufang , Mei Changlin , Miao Yu
Published: November 2019

Let $\{X_{ni}, 1 \leq i \leq m_{n}, n\geq 1\}${Xni,1≤i≤mn,n≥1} be an array of independent random variables with uniform distribution on $[0, \theta _{n}]$[0,θn], and $\{X_{n(k)}, k=1, 2, \ldots , m_{n}\}${Xn(k),k=1,2,…,mn} be the kth order statistics of the random variables $\{X_{ni}, 1 \leq i \leq m_{n}\}${Xni,1≤i≤mn}. We study the limit properties of ratios $\{R_{nij}=X_{n(j)}/X_{n(i)}, 1\leq i < j \leq m_{n}\}${Rnij=Xn(j)/Xn(i),1≤i<j≤mn} for fixed sample size $m_{n}=m$mn=m based on their moment conditions. For $1=i < j \leq m$1=i<j≤m, we establish the weighted law of large numbers, the complete convergence, and the large deviation principle, and for $2=i < j \leq m$2=i<j≤m, we obtain some classical limit theorems and self-normalized limit theorems.
Effects of dietary tributyrin on intestinal mucosa development, mitochondrial function and AMPK-mTOR pathway in weaned pigs
Authors: Wang Chunchun , Cao Shuting , Shen Zhuojun , Hong Qihua , Feng Jie , Peng Yan , Hu Caihong
Published: November 2019

Background

The objective of this experiment was to investigate the influence of dietary tributyrin on intestinal mucosa development, oxidative stress, mitochondrial function and AMPK-mTOR signaling pathway.

Methods

Seventy-two pigs were divided into two treatments and received either a basal diet or the same diet supplemented with 750 mg/kg tributyrin. Each treatment has six replicates of six pigs. After 14 days, 6 pigs from each treatment were selected and the jejunal samples were collected.

Results

Results showed that supplemental tributyrin increased (P < 0.05) villus height and villus height: crypt depth of weaned pigs. Pigs fed tributyrin had greater (P < 0.05) RNA/DNA and protein/DNA ratios than pigs on the control group. The mRNA levels of sodium glucose transport protein-1 and glucose transporter-2 in the jejunum were upregulated (P < 0.05) in pigs fed the tributyrin diet. Dietary tributyrin supplementation lowered (P < 0.05) the malondialdehyde and hydrogen peroxide (H2O2) content in jejunum, enhanced (P < 0.05) the mitochondrial function, as demonstrated by decreased (P < 0.05) reactive oxygen species level and increased (P < 0.05) mitochondrial membrane potential. Furthermore, tributyrin increased (P < 0.05) mitochondrial DNA content and the mRNA abundance of genes related to mitochondrial functions, including peroxisomal proliferator-activated receptor-γ coactivator-1α, mitochondrial transcription factor A, nuclear respiratory factor-1 in the jejunum. Supplementation with tributyrin elevated (P < 0.05) the phosphorylation level of AMPK and inhibited (P < 0.05) the phosphorylation level of mTOR in jejunum compared with the control group.

Conclusions

These findings suggest that dietary supplementation with tributyrin promotes intestinal mucosa growth, extenuates oxidative stress, improves mitochondrial function and modulates the AMPK-mTOR signal pathway of weaned pigs.
Man-made blue and purple barium copper silicate pigments and the pabstite (BaSnSi3O9) mystery of ancient Chinese wall paintings from Luoyang
Authors: Zhang Zhiguo , Ma Qinglin , Berke Heinz
Published: November 2019

Man-made ancient Chinese barium copper silicate pigments: Chinese (Han) Purple, BaCuSi2O6; Chinese (Han) Blue, BaCuSi4O10; Chinese Dark Blue, BaCu2Si2O7 (in summary called Chinese blues), and platelet-like crystals of BaSnSi3O9 were detected on mural paintings of a tomb in Luoyang City, Henan Province, China, dated to Western Han Dynasty (206 BC–8 AD). The pigments of the LY01 and LY02 samples were analyzed by archaeometrical methods: powder X-ray diffractometry (XRD), scanning electron microscopy (SEM–EDX) and micro-Raman spectroscopy. While the artificial nature of the ancient barium copper silicates was undoubted, the synthetic or mineral origin of BaSnSi3O9 of these murals had to be clarified. Involvement of the rare mineral pabstite Ba(Sn,Ti,Zr)Si3O9 from the Tian Shan mountains could be ruled out due to absence of Ti and Zr in the elemental composition. Tin compounds as admixtures to the lead minerals—the latter required as flux additive for the preparation of the Chinese blues—or tin admixtures to pristine barium starting minerals could be excluded, as well as the use of tin containing mineral mushistonite (CuSn(OH)6), primarily intended to be applied as copper source. Related to the findings for the production of Egyptian Blue (CaCuSi4O10), bronze or bronze scrap including also corroded material was used intending copper recycling. For the synthesis of the Luoyang Chinese blues only low amounts of bronze or bronze scrap were required providing the additional advantage to form in presence of air a tin/lead oxide flux with lowered vitrification temperatures and viscosities. This marked the advent of an ‘innovative production technology’ avoiding addition of large amounts of lead minerals as an effective lead-only flux. Despite of the chemical similarity to production of Egyptian Blue, the tin/lead based developments for the Chinese blues were anticipated to be independent excluding technology transfer from ancient Egypt. For further substantiation of the appearance of pabstite in the Luoyang Chinese blues a contemporary independent synthesis was sought, carried out under conditions similar to those of the barium copper silicate syntheses (1000 °C, but absence of a flux) starting from cassiterite (SnO2), quartz (SiO2) and witherite (BaCO3).
Assessing the feasibility and acceptability of Changing Health for the management of prediabetes: protocol for a pilot study of a digital behavioural intervention
Authors: Cassidy Sophie , Okwose Nduka , Scragg Jadine , Houghton David , Ashley Kirsten , Trenell Michael I. , Jakovljevic Djordje G. , Hallsworth Kate , Avery Leah
Published: November 2019

Background

The prevalence of prediabetes is rapidly rising in the UK, largely associated with an increase in obesity. Lifestyle programmes that provide support to make and sustain dietary and physical activity behavioural changes are necessary to initiate and maintain weight loss. However, these programmes are often intensive and time consuming. Given the magnitude of the problem, there is a need for behavioural interventions that can be delivered at scale. Digital interventions can address some of the aforementioned issues. The primary aim of the present study is to assess the feasibility and acceptability of a digital intervention called Changing Health that provides structured education and lifestyle behaviour change support to adults with prediabetes.

Methods

A single-group pilot study will be undertaken. We aim to recruit 40 participants with prediabetes defined by HbA1c or fasting plasma glucose (FPG), aged between 18 and 75 years with a BMI ≥ 25. Participants will receive the digital intervention (a mobile phone app incorporating structured education and behavioural tools to support lifestyle behaviour change) with the aim of losing and maintaining 5–6% of their baseline body weight. Each participant will receive 100 min of lifestyle coaching over the 9-month intervention period and will have continued access to the digital intervention. Clinical outcome measures will be collected during four visits to our clinical research facility: two visits at baseline, one visit at month 3, and one visit at month 9. These secondary outcome measures will include diet, physical activity, sleep, metabolic control, body composition, cardiorespiratory fitness, and cardiovascular function. To measure primary outcomes, an embedded qualitative study will be conducted to obtain data on feasibility and acceptability of the intervention.

Discussion

This pilot study will establish whether Changing Health is feasible and acceptable to adults with prediabetes. Clinical outcome measures will provide estimates of variability to inform sample size calculations, and qualitative data generated will inform any necessary refinements to the intervention. This will provide a platform for a larger evaluation to assess the effectiveness of Changing Health for changing diet and physical activity to initiate and maintain weight loss in adults with prediabetes.

Trial registration

ISRCTN Registry: ISRCTN69270299.
A combinatorial immunotherapy for malignant brain tumors: D2C7 immunotoxin and immune checkpoint inhibitors.
Authors: Bao Xuhui , Keir Stephen T. , Nair Smita K , Pastan Ira , Bigner Darell D. , Chandramohan Vidyalakshmi
Published: November 2019

102

Background: Immunotoxins can induce direct and rapid cytotoxicity by targeting specific tumor antigens. D2C7 is a unique recombinant immunotoxin targeting EGFRwt/EGFRvIII, two frequently overexpressed proteins on gliomas, and is currently being tested in a phase I/II clinical trial (NCT02303678) for recurrent malignant gliomas. Immunotoxins have also been shown to induce a secondary antitumor immune response via stimulation of cytotoxic T lymphocytes (CTLs). Immune checkpoint inhibitors, which have successfully treated several advanced tumors by promoting the antitumor function of CTLs, may further enhance this immunotoxin-induced antitumor response. Thus, we hypothesize that combining D2C7 with immune checkpoint inhibitors will promote long-term tumor regression due to primary cytotoxicity and enhanced anti-tumor immunity. Methods: We developed a CT2A-mD2C7 mouse glioma cell line with robust in vitro cytotoxicity of D2C7 (IC50= 0.47 ng/mL). In vivo anti-tumor efficacy was evaluated by intratumoral injection of D2C7 combined with intraperitoneal injection of anti-CTLA4 or anti-PD1 antibodies in single-side and bilateral subcutaneous (SC) CT2A-mD2C7 glioma models in C57BL/6 immunocompetent mice. Results: In the single-side model, D2C7 monotherapy and combinatorial therapy showed a significant tumor growth delay (P < 0.01). Complete regression ( ≥ 40%) was only observed in combinatorial therapy groups. All cured mice rejected the rechallenging of CT2A parental cells in the contralateral flank and the subsequent rechallenging of CT2A-mD2C7 cells in the brain. In the bilateral model, the larger right tumors were treated with D2C7/anti-CTLA4/anti-PD1 monotherapy or D2C7+anti-CTLA4/PD1 combinatorial therapy, while the left tumors were untreated by D2C7. In the groups where the right tumors were treated with monotherapy or combinatorial therapy, the left untreated tumors also grew much slower. Furthermore, the combinatorial therapy led to the most significantly delayed growth of the left untreated tumors (P < 0.05). Conclusions: Immune checkpoint inhibitors can enhance D2C7-induced anti-tumor immunity to achieve a synergistic long-term tumor regression.
Hypoxia-inducible factor 1α in regulation of programmed death: Ligand 1 in glioma under hypoxia microenvironment.
Authors: Hu Man , Xue Song , Yu Jinming , Fan Bingjie , Ma Ji , Xie Li
Published: November 2019

103

Background: Glioma is a highly lethal tumor that is known for its immune inhibitory capabilities. Despite great progress in treatment modalities, the median survival time of high-grade gliomas patients is only about 11.1 months. Gliomas are aberrantly expressed programmed death–ligand 1 (PD-L1) which results in tumor-induced immune suppression. Hypoxia is well known to induce aggressiveness, promotes tumor progression and resistance to chemotherapy and radiotherapy. Recently, studies have indicated that hypoxia play a prominent role in tumor immune escape. The aim of the study was to explore the relationship between PD-L1 and hypoxia inducible factor 1α (HIF-1α) and the role in the progression of gliomas. Methods: We adopted immunohistochemistry methods to detect expressions of PD-L1 and HIF-1α in 64 surgical specimens (23 cases for low-grade and 41 cases for high-grade gliomas, respectively). Immunoreactivity was analyzed in association with patients’ clinical characteristics or survival time. Expression of the PD-L1 and HIF-1α was analyzed in three GBM cell lines, U343, U373, and U251, under in vitro hypoxia (12, 24 or 72 h at 0.1% O2). Reverse transcriptase-polymerase chain reaction (RT-PCR) was carried out to detect the mRNA expression of PD-L1 and HIF-1α. Results: PD-L1 and HIF-1α protein expression was detected in 81.25% and 84.73% of glioma specimens, respectively. The expression of PD-L1 protein is positively correlated with HIF-1α (r = 0.52; p= 0.013). Kaplan–Meier analysis revealed a significant effect of PD-L1 grade on cumulative overall survival. Patients with negative PD-L1 expression survive longer than those with positive expression ( p= 0.007). PD-L1 and HIF-1α mRNA was most consistently upregulated in relation to duration of in-vitro hypoxia (72h, p= 0.007). There was a significant and positive relationship between the PD-L1 and HIF-1α mRNA expression (r = 0.45; p= 0.01). Conclusions: The present study showed a role for hypoxia/HIF-1α in driving immune escape and provided a potential novel cancer immunotherapy targeting hypoxia to block PD-L1 expression, which may boost the immune system in cancer patients.
Association of diversity and composition of the gut microbiome with differential responses to PD-1 based therapy in patients with metastatic melanoma.
Authors: Gopalakrishnan Vancheswaran , Spencer Christine , Reuben Alexandre , Karpinets Tatiana , Hutchinson Diane , Hoffman Kristi , Prieto Peter A. , Tetzlaff Michael T. , Lazar Alexander , Davies Michael A. , Gershenwald Jeffrey E. , Jenq Robert R. , Hwu Patrick , Sharma Padmanee , Allison James Patrick , Futreal Andrew , Ajami Nadim , Petrosino Joseph , Daniel-MacDougall Carrie , Wargo Jennifer A.
Published: November 2019

2

Background: Tremendous advances have been made in cancer therapy through the use of immune checkpoint blockade, although responses are not always durable. There is a growing appreciation of the role of the microbiome in cancer-related outcomes and recent evidence in murine models suggests that modulation of the gut microbiome may enhance responses to immune checkpoint blockade in melanoma. However this has not been investigated in patients. Here, we demonstrate that differential bacterial “signatures” exist in the gut microbiome of responders (R) and non-responders (NR) to anti-PD1 therapy at baseline, and that insights gained could be used to derive actionable strategies to enhance responses. Methods: We collected oral (n = 222) and gut microbiome (n = 113) samples on a large cohort of patients with metastatic melanoma (n = 228), with a majority treated with anti-PD1 therapy (n = 110). Patients were classified as either R or NR based on RECIST criteria, and 16S rRNA gene sequencing was performed to characterize the diversity and composition of the microbiomes. Immune profiling (via 7-marker IHC panel of CD3, CD8, PD-1, PD-L1, Granzyme B, RORγT and FoxP3) was performed in available tumors at baseline. Results: In these studies, we observed significant differences in the diversity and composition of the gut microbiome in R versus NR to PD1 blockade at baseline, but no clear differences in oral microbiomes. Specifically, R had a significantly higher alpha diversity compared to NR (p = 0.017). Notable differences were also seen in the composition of the gut microbiome of R versus NR. Immune profiling demonstrated significantly increased immune infiltrates in baseline tumor samples of R, with a positive correlation between CD8, CD3, PD1 and FoxP3 T-cell density and abundance of specific bacteria enriched in R (e.g. Faecalibacterium). Conclusions: Differences exist in the diversity and composition of the gut microbiome in R vs NR to anti-PD1 therapy. These results have far-reaching implications and suggest that modifications to the gut microbiome could potentially enhance therapeutic responses to immune checkpoint blockade.
Association of tumor mutational burden with smoking and mutation status in non-small cell lung cancer (NSCLC).
Authors: Davis Andrew A. , Chae Young Kwang , Agte Sarita , Pan Alan , Mohindra Nisha Anjali , Villaflor Victoria Meucci , Giles Francis J.
Published: November 2019

24

Background: Reponses to immunotherapy have been observed in multiple solid tumors including non-small cell lung cancer (NSCLC). Identifying optimal biomarkers for response to anti-PD-1/PD-L1 therapies remains critical. Tumor mutational burden (TMB) may indicate genomic instability and potential neoantigen binding sites to activated effector T cells. Methods: We retrospectively examined tumor mutational burden (TMB) using next-generation sequencing (Foundation Medicine) for 83 patients with NSCLC in our institution. TMB included both coding and non-coding regions, but excluded potentially functional mutations. We correlated TMB (mutations per megabase) with smoking history, number of potentially functional mutations, variants of unknown significance, and the driver mutations EGFR, ALK, and KRAS. TMB high versus low was stratified based on 15 mutations per megabase pair. Results: Our findings demonstrated that TMB was significantly associated with current/former smoking status (p = 0.01, Table 1). TMB was also significantly associated with number of potentially functional mutations, number of variants of unknown significance (VUS), and total reported mutations (p < 0.01). The absence of mutations in EGFR, ALK, or KRAS tended to be associated with higher TMB as well (p = 0.07). Conclusions: TMB was associated with smoking status, as well as potentially functional mutations, VUS, and total number of reported mutations. Our results indicate that number of coding region mutations predict genomic instability in non-coding regions. Future studies are needed to correlate this measure with other immune biomarkers and patient outcome in NSCLC. [Table: see text]
Age-related differences in cannabis use by cancer patients referred for supportive care.
Authors: Portman Diane , Donovan Kristine A.
Published: November 2019

104

Background: Increasingly, cancer patients are using cannabis in their efforts to manage symptoms. Studies of legal recreational cannabis suggest young adults (YA) may disproportionately account for increases in cannabis use. There are few studies of cannabis use in cancer patients and its effect on symptoms, however, and most have not stratified their results by age. To address this, we examined rates of cannabis use across three age groups: YA ages 18 to 39, adults 40 to 65, and adults older than 65 (OA). We also examined the effects of age and cannabis use on patients’ report of cancer-related symptoms. Methods: We conducted a retrospective review of 1223 cancer patients referred to outpatient supportive care for symptom management between 2014 and 2017. Patients underwent urine drug testing for tetrahydrocannabinol (THC) and completed the Edmonton Symptom Assessment Scale-Revised-CSS during their initial visit. Results: In Chi square analysis, age was significantly associated with cannabis use (p < .001): 30% of YA tested positive for THC compared to 21% of adults and 8% of OA. As a group, cannabis users reported significantly higher scores for pain, tiredness, nausea, lack of appetite, anxiety, depression, difficulty sleeping, and worse overall well-being (p values < .05). In MANOVA, there was a significant interaction effect between age and cannabis use for pain, lack of appetite, shortness of breath, anxiety, depression, difficulty sleeping, and overall well-being (p values < .05). While YA and adults who tested positive for THC reported higher symptom scores for each of these symptoms, OA patients who were THC positive reported lower scores for pain, anxiety, depression, and better overall well-being. Conclusions: Findings suggest that compared to adults and OA, more YA patients are using cannabis in attempts to control cancer-related symptoms. With the exception of OA, cannabis users rate their cancer-related symptoms as more severe than nonusers. Findings support the need for patient education about potential therapeutic benefits and adverse effects of cannabis use in cancer. Prospective, observational studies are needed to characterize patients’ use before and after a cancer diagnosis.
Proactive versus reactive feeding tube (FT) placement in head and neck cancer patients (HNC pts) receiving chemoradiation (CRT).
Authors: Sivananth Thunnisa , Quinn Maureen , Stortz Rae-Ann , Palma David A. , Francis Peggy , Kuruvilla Sara , Nichols Anthony C. , Warner Andrew , Winquist Eric
Published: November 2019

11

Background: Most HNC pts treated with CRT develop severe treatment-related oropharyngeal mucositis. For pts with adequate nutritional status and swallowing function prior to CRT the optimal approach to nutritional management remains undefined. A subset of pts will require FTs to complete treatment, but at least 50% of pts with prophylactic FTs never use them (Madhoun 2011). At our center we have used a "reactive" approach which minimizes exposure to unnecessary FT placement. However, some pts suffer nutritional crises resulting in hospitalization, treatment interruption, and higher risks of complications from FT placement. We investigated the impact of a more proactive approach to FT placement in our pts. Methods: HNC pts treated with CRT who received a FT during treatment 2014-2018 were retrospectively identified from electronic medical records and clinical data extracted. "Proactive" FTs were not considered medically necessary but were placed within 15 days of starting CRT. Primary outcomes of interest were weight loss during CRT (WTL), FT complications, length of hospital stay and FT duration. Uni- and multivariate analyses were done and p values < 0.05 considered of interest. Results: 124 pts were identified: 87% male, median age 62.5 yrs (39-80) and 67% oropharyngeal primary. All received platinum-based chemotherapy or cetuximab (8 pts). 19 FTs were considered medically necessary, 94 were placed reactively and 11 placed proactively; 91% were percutaneous and 94% were used. Median weight was 79.0 kg (27.6-165.7) prior to CRT and 71.2 kg (26.8-148.2) after. Median WTL was 9.9% (-13.9 to 33.3%). Proactive FT placement was associated with less WTL (p = 0.045). WTL was greater in pts over age 65 (OR 11.6 [1.4-97.6]). Hospital stay was longer for pts who had reactive FT. Females had longer FT duration (p = 0.005). Conclusions: These data suggest that when a reactive approach to FT placement is used, earlier FT placement during CRT is more effective at reducing weight loss and hospitalization time in this population. Specific criteria for pt selection with this approach should be defined. Further research to define the optimal approach to nutritional management in HNC pts receiving CRT is needed.
High/low dose dexamethasone with physical activity for cancer-related fatigue in patients with advanced cancer: A phase II randomized double blind study.
Authors: Yennu Sriram , Valero Vicente , Lim Bora , Booser Daniel J. , Hernandez Carolina Diaz , Lu Zhanni , Liu Diane D. , Busaidy Naifa Lamki , Reuben James M. , Williams Janet L. , Hess Kenneth R. , Basen-Engquist Karen , Bruera Eduardo
Published: November 2019

110

Background: Cancer-related-fatigue (CRF) is the most debilitating symptom in patients with advanced cancer. Physical activity (PA) improves CRF with lower adherence in advanced cancer. Dexamethasone (Dex) improves CRF but has long-term side effects. The purpose of the study was to determine whether a brief course of Dex improves adherence to PA for CRF management. Methods: Advanced cancer patients with CRF ≥ 4/10 on Edmonton Symptom Assessment Scale (ESAS) were eligible. Patients were randomized to either 4mg of Dex (LoDex) or 8mg of Dex (HiDex) orally BID for 7 days Plus standardized aerobic and resistance exercise for 4 weeks. Change in the Functional Assessment of Chronic Illness-Fatigue (FACIT-F) fatigue subscale from baseline to Day 8 (primary outcome) and Day 29 were assessed. Secondary outcomes included changes in fatigue (ESAS, PROMIS, MFSI), Sleep Quality (PSQI), fasting blood glucose, and myopathy. Results: Total evaluable patients were 60 (31 LoDex and 29 HiDex arms). The study was feasible (N = 60/67 were evaluable); 84% and 65% LoDex, and 96% and 68% Hi Dex were adherent to aerobic and resistance exercise, respectively [All Patients were adherent to study medication]. There was no significant difference in grade 3+ AE’s between the two arms (P = 0. 92). The FACIT fatigue subscale Cohen’s d in Lo Dex was 0.90 (P < 0.001) and 0.94(P < 0.001); and Hi Dex was 0.86(P < 0.001); and 1.05(P < 0.001) at Day 8 and Day 29, respectively. Similar improvement was found for ESAS Fatigue (P < 0.001), MFSI total (P = 0.005), and PROMIS –fatigue total (P = 0.005). Mixed model analysis showed significant improvement in FACIT-F fatigue scores at Day 8 (P = 0.0006), Day 15 (P = 0.0002), and D (P = 0.0018). There was no significant difference between the two arms at Day 8 and Day 29 in fatigue scores, myopathy, fasting blood glucose levels, symptom distress, and sleep quality scores. Conclusions: Short course of dexamethasone Plus physical activity resulted in sustained and robust improvement in CRF outcomes for upto 3 weeks after discontinuation of steroids suggesting possible priming effects of steroids helped to sustain physical activity. Further larger studies are justified. Clinical trial information: NCT02491632.
Health care utilization and patient-related outcomes in patients with malignant bowel obstruction admitted to a United States safety net hospital.
Authors: Mukthinuthalapati Vijaya Venkatasubbaraya Pavan Kedar Vijaya Venkatasubbar , Putta Aakash , Vohra Ishaan , Katiyar Vatsala , Moturi Krishna , Mullane Michael Russell , Gupta Shweta
Published: November 2019

50

Background: Malignant bowel obstruction (MBO) and gastric outlet obstruction (GOO) can be a late complication of intra-abdominal malignancy with a poor prognosis. Most studies about its outcomes have focused on survival. There is paucity of studies assessing health care utilization and end of life care decisions. Methods: We retrospectively collected data from the electronic medical record of patients admitted with MBO or GOO at a safety-net hospital in Chicago, US between January 2013 and December 2017. The charts were analyzed for outcomes related to end of life care and health care utilization. The outcomes were compared by across three broad treatment arms: those that received surgical intervention, those that received venting gastrostomy (VG) and those that were treated medically alone. Results: Forty-six patients were identified of which 31 were admitted with MBO. 25 (54%) of them were due to stage IV cancers. Mean age of study population was 61 years. Surgical management, VG and medical management were done in 17, 8 and 21 patients respectively. There was no difference in ICU admission rate, length of stay of index admission, 90 day-readmission rate or mean visits to the ER between the groups. Patients receiving venting gastrostomy tube had highest rate of oral solid food tolerability. Twenty-eight patients died or were enrolled in hospice within a median of 115 days. Conclusions: All modalities of treatment had similar health utilization measures in patients with MBO and GOO. Surgical management, if feasible, has the longest time to hospice enrollment or death and should be offered to patients who are suitable. [Table: see text]
Breast Cancer Care Quality in South Africa’s Public Health System: An Evaluation Using American Society of Clinical Oncology/National Quality Forum Measures
Authors: O’Neil Daniel S. , Chen Wenlong Carl , Ayeni Oluwatosin , Nietz Sarah , Buccimazza Ines , Singh Urishka , Čačala Sharon , Stopforth Laura , Joffe Maureen , Crew Katherine D. , Jacobson Judith S. , Neugut Alfred I. , Ruff Paul , Cubasch Herbert
Published: November 2019

PURPOSE

The quality of breast cancer care in sub-Saharan Africa contributes to the region’s dismal breast cancer mortality. ASCO has issued quality measures focusing on delivery of adjuvant chemotherapy, radiotherapy, and endocrine therapy. We applied these measures in five South African public hospitals and analyzed factors associated with care concordance.

MATERIALS AND METHODS

Among 1,736 women with breast cancer who were enrolled in the South African Breast Cancer and HIV Outcomes study over 24 months, we evaluated care using ASCO’s three measures. We also evaluated adjuvant chemotherapy receipt in 957 women with an indication. We used logistic regression to estimate associations between measure-concordant care and patient factors.

RESULTS

Of 235 women with hormone receptor–negative cancer, 173 (74%) began adjuvant chemotherapy within 120 days from diagnosis. Of 194 patients who received breast-conserving surgery, 73 (37%) began radiotherapy within 365 days from diagnosis. Of 999 women with hormone receptor–positive cancer, 719 (72%) initiated endocrine therapy within 365 days from diagnosis. Chemotherapy and radiotherapy measure-concordant care were more common among women residing < 20 km from the hospital (odds ratio [OR], 1.79; 95% CI, 1.32 to 2.44 and OR, 3.17; 95% CI, 1.57 to 6.42). Endocrine therapy measure-concordant care was more common among English-speaking women (OR, 2.12; 95% CI, 1.12 to 4.02). Participating hospitals varied in care concordance. HIV infection did not affect care quality.

CONCLUSION

More timely delivery of chemotherapy, radiotherapy, and endocrine therapy is needed in South Africa, particularly for women living > 20 km from the hospital or not speaking English. Focused quality improvement efforts could support that goal.
Imagining Otherwise
Authors: Van Asselt Bess Collins
Published: November 2019

This article explores the life history of Sam, a queer and transgender youth of color who contests standardized futures in secondary schools. Sam's school life is rife with expectations that seek to confine Sam and their way of being in the world. In response to their school life, Sam forwards new ways of thinking of the future that rely on remaining present, contesting identity politics and questioning the contours of humanity.
Strain and shear wave ultrasound elastography in evaluation of chronic inflammatory disorders of major salivary glands
Authors: Elbeblawy Yasmein Maher , Eshaq Amer Mohamed Maha
Published: November 2019

Objective:

The aim of this study was to assess chronic inflammatory conditions of major salivary glands by ultrasound elastography.

Methods:

21 patients with chronic inflammatory conditions of major salivary glands and 21 healthy adult volunteers were included in this study. All participants underwent B-mode sonography and ultrasound elastography. The diagnostic performance of strain ratio and shear wave velocity was evaluated by sensitivity and specificity at the optimum cutoff point and the area under the receiver operating characteristic curve.

Results:

Cases showed statistically significant higher median strain ratio of parotid and submandibular gland than control group (p-value = 0.001). Total cases showed statistically significant higher median scores than control group (p-value < 0.001). At cut-off value of (1.13); diagnostic accuracy, sensitivity and specificity were 97.6, 95.2 and 100% respectively with AUROC 0.954 and confidence interval: 0.840–0.995. Cases showed statistically significant higher median shear wave velocity of parotid gland than control group (p-value = 0.022), with no statistically significant difference in submandibular gland in the two groups (p-value = 0.216). Total cases showed statistically significant higher median scores than control group (p-value < 0.001). At cut-off value of (23.5), diagnostic accuracy was 78.6% with a sensitivity of 81% and specificity of 76.2% with 0.819 AUROC and onfidence interval :0.669–0.920.

Conclusion:

Our initial experience suggests that elastography may be potentially useful for diagnosis of chronic inflammatory conditions of the major salivary glands. This conclusion needs to be further validated large sample studies.
Advances in bladder substitution and creation of neobladders in children
Authors: Reifsnyder Jennifer E. , Hanna Moneer K.
Published: November 2019

Cystectomy and urinary bladder substitution are rare in children but may be necessary in some cases of bladder exstrophy, in the setting of malignancy, or in other settings in which the bladder is severely dysfunctional. This article details advances in surgical techniques in creating continent urinary diversions in this specialized pediatric population.
Control of actin dynamics during cell motility
Authors: Buracco Simona , Claydon Sophie , Insall Robert
Published: November 2019

Actin polymerization is essential for cells to migrate, as well as for various cell biological processes such as cytokinesis and vesicle traffic. This brief review describes the mechanisms underlying its different roles and recent advances in our understanding. Actin usually requires “nuclei”—preformed actin filaments—to start polymerizing, but, once initiated, polymerization continues constitutively. The field therefore has a strong focus on nucleators, in particular the Arp2/3 complex and formins. These have different functions, are controlled by contrasting mechanisms, and generate alternate geometries of actin networks. The Arp2/3 complex functions only when activated by nucleation-promoting factors such as WASP, Scar/WAVE, WASH, and WHAMM and when binding to a pre-existing filament. Formins can be individually active but are usually autoinhibited. Each is controlled by different mechanisms and is involved in different biological roles. We also describe the processes leading to actin disassembly and their regulation and conclude with four questions whose answers are important for understanding actin dynamics but are currently unanswered.
Update on the diagnosis and management of exocrine pancreatic insufficiency
Authors: Perbtani Yaseen , Forsmark Chris E.
Published: November 2019

Exocrine pancreatic insufficiency (EPI) is characterized by inadequate pancreatic enzyme delivery to the small intestine Exocrine pancreatic insufficiency (EPI) is characterized by inadequate pancreatic enzyme delivery to the small intestine, resulting in malabsorption. Clinical manifestations of EPI are often nonspecific and can lead to lack of timely recognition and diagnosis. Central to this clinical dilemma is the lack of highly accurate or specific testing which leads to misdiagnosis and suboptimal treatment. Identification of high-risk patients is key in the diagnosis of EPI and this includes patients with pancreatic parenchyma disorders such as chronic pancreatitis, pancreatic malignancy, cystic fibrosis, and those undergoing pancreatic resection for benign and malignant disease. Less recognized are the number of additional conditions which may also have EPI as a consequence. Owing to an increase in morbidity and impaired quality of life associated with this condition, goals of treatment have been aimed at repleting exocrine enzyme deficiency by oral pancreatic enzyme replacement therapy (PERT). The basis of PERT is to provide activated digestive enzymes to the small bowel during the prandial period, mainly, leading to sufficient absorption of fat and fat-soluble vitamins. The benefits of PERT have been shown to go beyond the improvement in signs and symptoms associated with EPI and include decreasing prevalence of osteopathy and improving survival outcomes in subsets of patients with this condition. However, despite the overall benefits in treatment, the diagnosis and management of EPI are suboptimal. Current literature suggests patients at high risk of developing EPI are not tested and those who are diagnosed are not treated with adequate dosages. In this review, we highlight patients who are at high risk for the development of EPI, analyze consequences and treatment of this disorder, review rationale for enzyme replacement therapy, and examine current evidence for treatment optimization.
Adapting the 3D-printed Openflexure microscope enables computational super-resolution imaging
Authors: Grant Stephen D. , Cairns Gemma S. , Wistuba Jordan , Patton Brian R.
Published: November 2019

We report on a 3D printed microscope, based on a design by the Openflexure project, that uses low cost components to perform fluorescence imaging. The system is sufficiently sensitive and mechanically stable to allow the use of the Super Resolution Radial Fluctuations algorithm to obtain images with resolution better than the diffraction limit. Due to the low-cost components, the entire system can be built for approximately $1200.
МЕТОДОЛОГИЯ ИСПОЛЬЗОВАНИЯ ИНТЕЛЛЕКТУАЛЬНЫХ КОМПЬЮТЕРНЫХ ИГР В ОБУЧЕНИИ ИНФОРМАЦИОННЫМ ТЕХНОЛОГИЯМ
Authors: Gibadullin Artur Amirzyanovich
Published: November 2019

Данная статья посвящена комплексу методических разработок, которые позволяют проводить обучение информационным технологиям при помощи соответствующих интеллектуальных игр. Автор отмечает их положительный эффект. Он заключается в том, что они способствуют развитию обучающихся, стимулируют их мотивацию. Характерной особенностью является отсутствие эффекта привыкания и потери чувства реальности. При этом интеллектуальная компонента находится на первом месте и становится определяющей.