bluuebunny/crossref_metadata_2025 huggingface dataset:
Quality of life data for individuals affected by spinal muscular atrophy: a baseline dataset from the Cure SMA Community Update Survey
Authors: Belter Lisa , Cruz Rosángel , Jarecki Jill
Published: August 2020

Background

Individuals and/or caregivers of individuals affected by spinal muscular atrophy (SMA) completed the 2019 Cure SMA Community Update Survey, online, assessing health-related quality of life (HRQoL), loss of work productivity, and fatigue using the Health Utilities Index Questionnaire (HUI), the Work Productivity and Activity Impairment Questionnaire (WPAI), and the Patient Reported Outcomes Measurement Information System Fatigue Short Form (PROMIS Fatigue SF), respectively. The purpose was to collect baseline quality of life results among individuals affected by SMA using the above Patient Reported Outcome Measures (PROMs).

Results

Of 666 surveys completed between March and May 2019, 478 were included in this analysis, accounting for duplicates, missing data, or deaths. The breakdown across SMA type I, II and III was 25, 47 and 28%, respectively. Responses were characterized by current functional status/milestone, with subsets for “permanent ventilation,” “non-sitters,” “sitters,” “walk with support,” and “walk alone.” WPAI and HUI respondents included affected adults and caregivers. The PROMIS Fatigue SF was completed by the primary caregiver of affected children.

Overall, those affected by a less severe form of SMA and with a higher functional status reported higher HRQoL and lower work productivity and activity impairment. All affected individuals reported higher fatigue levels than the general population.

Conclusions

This study offers useful insights into the burden of SMA among affected individuals and their caregivers. The results provide a baseline picture of the patient and caregiver experience with SMA in a post-treatment era from which to measure year-over-year changes in quality of life scores from new therapies and improved care. The WPAI demonstrates the significant impact of work productivity among SMA populations. Aspects of the HUI seem more appropriate to certain SMA sub-populations than others. Measures from the PROMIS Fatigue SF appear to under-represent the burden of fatigue often reported by SMA individuals and caregivers; this may, perhaps be due to a lack of sensitivity in the questions associated with fatigue in the SMA affected population, when compared with other studies on this topic. Overall, these results suggest the need for SMA-specific quality of life outcome measures to fully capture clinically meaningful change in the SMA population.
Impact of the Maternal and Child Health handbook in Angola for improving continuum of care and other maternal and child health indicators: study protocol for a cluster randomised controlled trial
Authors: Balogun Olukunmi Omobolanle , Tomo Caroline Kaori , Mochida Keiji , Mikami Masashi , da Rosa Vasconcelos Henda , Neves Isilda , Hiraoka Hisakazu , Aiga Hirotsugu , Mori Rintaro , Takehara Kenji
Published: August 2020

Background

The Maternal and Child Health (MCH) handbook is an integrated home-based record (HBR) designed to record in a single document all the information regarding health services provided to a pregnant woman and her child. The MCH handbook has the potential to support continuity of care which is key to strengthening maternal, newborn and child health. However, there is a lack of an integrated system to manage the health of pregnant women and young children on an ongoing basis in Angola. Thus, the Angolan Ministry of Health is partnering with the Japan International Cooperation Agency to build the capacity of healthcare providers through trainings and implementation of the MCH handbook to improve service utilisation. In this study, we will estimate the impact of an intervention package including distribution of MCH handbook and its supplementary interventions to women, on the utilisation of services provided at healthcare facilities from pregnancy through the postnatal and early childhood period.

Methods

This study is a cluster randomised controlled trial involving public healthcare facilities across all the municipalities located in Benguela Province, Angola. All women who go to participating healthcare facilities and with confirmed pregnancy around the beginning of the trial period will be included in the study. Women will be randomised according to the municipality where their primary maternity and/or childcare services are located. The intervention package will consist of MCH handbook distribution at all public healthcare facilities, MCH handbook utilisation training for healthcare providers and community mobilisation for women on the use of the MCH handbook. The intervention will be administered to all women in the intervention arm while those in the control arm will continue the traditional use of two stand-alone HBRs. The primary outcome measure for this study is to compare the proportion of women who achieve a complete continuum of care in both study arms.

Discussion

The findings from the study are expected to form a basis for revising the current trial version of the Angola MCH handbook and provide a framework for policy guiding nationwide scale-up and distribution of the MCH handbook.

Trial registration

ISRCTN Registry ISRCTN20510127. Registered on 4 June 2019
Vertical displacement of pleura: a new method for bronchospasm evaluation?
Authors: Martins Sara Raquel , Nogué Ramon
Published: August 2020

Background

Lung ultrasonography has been increasingly recognized has a valuable diagnostic tool. In adult patients with asthma/chronic obstructive pulmonary disease and wheezing, LUS usually presents as an A/nude profile (normal profile, with sliding and A-lines, and without any abnormal findings) or at most reveals a decrease/absence of lung sliding. Therefore, until now simple point-of-care ultrasonography appeared to be unable to assess the severity of airflow limitation.

Case presentation

We report the case of a woman presenting to the emergency department with an asthma exacerbation. Bedside ultrasound showed the usual A/normal profile, but also an associated vertical pleural displacement, probably secondary to hyperinflation and accessory muscle recruitment. We evaluated the described movement with M-mode and established a comparison index between end-inspiration and end-expiration, using the skin as reference. This index showed improvement and complete normalization during treatment.

Conclusions

Pleural vertical displacement appears to be a sonographic alteration associated to bronchospasm and accessory muscle recruitment. It is easily identifiable and measurable on LUS, thus possibly representing a new method to evaluate bronchospasm and monitoring treatment response. Further research is needed to confirm or refute this finding.
The two faces of synaptic failure in AppNL-G-F knock-in mice
Authors: Latif-Hernandez Amira , Sabanov Victor , Ahmed Tariq , Craessaerts Katleen , Saito Takashi , Saido Takaomi , Balschun Detlef
Published: August 2020

Background

Intensive basic and preclinical research into Alzheimer’s disease (AD) has yielded important new findings, but they could not yet been translated into effective therapies. One of the reasons is the lack of animal models that sufficiently reproduce the complexity of human AD and the response of human brain circuits to novel treatment approaches. As a step in overcoming these limitations, new App knock-in models have been developed that avoid transgenic APP overexpression and its associated side effects. These mice are proposed to serve as valuable models to examine Aß-related pathology in “preclinical AD.”

Methods

Since AD as the most common form of dementia progresses into synaptic failure as a major cause of cognitive deficits, the detailed characterization of synaptic dysfunction in these new models is essential. Here, we addressed this by extracellular and whole-cell patch-clamp recordings in AppNL-G-F mice compared to AppNL animals which served as controls.

Results

We found a beginning synaptic impairment (LTP deficit) at 3–4 months in the prefrontal cortex of AppNL-G-F mice that is further aggravated and extended to the hippocampus at 6–8 months. Measurements of miniature EPSCs and IPSCs point to a marked increase in excitatory and inhibitory presynaptic activity, the latter accompanied by a moderate increase in postsynaptic inhibitory function.

Conclusions

Our data reveal a marked impairment of primarily postsynaptic processes at the level of synaptic plasticity but the dominance of a presumably compensatory presynaptic upregulation at the level of elementary miniature synaptic function.
Efficacy of matrilin-3-primed adipose-derived mesenchymal stem cell spheroids in a rabbit model of disc degeneration
Authors: Muttigi Manjunatha S. , Kim Byoung Ju , Kumar Hemant , Park Sunghyun , Choi Un Yong , Han Inbo , Park Hansoo , Lee Soo-Hong
Published: August 2020

Background

Chronic low back pain is a prevalent disability, often caused by intervertebral disc (IVD) degeneration. Mesenchymal stem cell (MSC) therapy could be a safe and feasible option for repairing the degenerated disc. However, for successful translation to the clinic, various challenges need to be overcome including unwanted adverse effects due to acidic pH, hypoxia, and limited nutrition. Matrilin-3 is an essential extracellular matrix (ECM) component during cartilage development and ossification and exerts chondrocyte protective effects.

Methods

This study evaluated the effects of matrilin-3-primed adipose-derived MSCs (Ad-MSCs) on the repair of the degenerated disc in vitro and in vivo. We determined the optimal priming concentration and duration and developed an optimal protocol for Ad-MSC spheroid generation.

Results

Priming with 10 ng/ml matrilin-3 for 5 days resulted in the highest mRNA expression of type 2 collagen and aggrecan in vitro. Furthermore, Ad-MSC spheroids with a density of 250 cells/microwell showed the increased secretion of favorable growth factors such as transforming growth factor beta (TGF-β1), TGF-β2, interleukin-10 (IL-10), granulocyte colony-stimulating factor (G-CSF), and matrix metalloproteinase 1 (MMP1) and decreased secretion of hypertrophic ECM components. In addition, matrilin-3-primed Ad-MSC spheroid implantation was associated with optimal repair in a rabbit model.

Conclusion

Our results suggest that priming MSCs with matrilin-3 and spheroid formation could be an effective strategy to overcome the challenges associated with the use of MSCs for the treatment of IVD degeneration.
COCO enhances the efficiency of photoreceptor precursor differentiation in early human embryonic stem cell-derived retinal organoids
Authors: Pan Deng , Xia Xi-Xi , Zhou Heng , Jin Si-Qian , Lu Yang-Yan , Liu Hui , Gao Mei-Ling , Jin Zi-Bing
Published: August 2020

Background

Significant progress has been made in cell replacement therapy for neural retinal diseases using retinal cells differentiated from human pluripotent stem cells. Low tumorigenicity and the ability to mature to form synaptic junctions make precursor cells a promising donor source. Here, we attempted to improve the yield of photoreceptor precursor cells in three-dimensional retinal organoids from human embryonic stem cells (hESCs).

Methods

A CRX-tdTomato-tagged hESC line was generated to track retinal precursors in 3D retinal organoids. COCO, a multifunctional antagonist of the Wnt, TGF-β, and BMP pathways, was employed to 3D organoid differentiation schemes for enhanced photoreceptor precursor cells. Organoid fluorescence intensity measurement was used to monitor retinalization tendency with the number of precursors further checked by flow cytometry. Signature gene expression during organoid differentiation were assessed by qPCR and immunocytochemistry after COCO supplementation.

Results

CRX-positive cells can be spatiotemporally tracked by tdTomato without affecting retinalization during retinal organoid differentiation. Fluorescence intensity of organoids, which turned out highly consistent with flow cytometry measurement, allowed us to determine the differentiation efficiency of precursors during organoid culturing directly. Using COCO as an auxiliary supplement, rather than alone, can yield an increased number of photoreceptor precursors in the early stage of organoid differentiation. Over a longer time-frame, photoreceptor precursors enhanced their fate of cones and decreased fate of rods after treatment with COCO.

Conclusions

Tracing with the CRX-reporter system showed that in retinal organoids derived from human pluripotent stem cells, COCO increased the differentiation efficiency of photoreceptor precursors and cones.
Infrared and visible image fusion based on nonlinear enhancement and NSST decomposition
Authors: Xing Xiaoxue , Liu Cheng , Luo Cong , Xu Tingfa
Published: August 2020

In multi-scale geometric analysis (MGA)-based fusion methods for infrared and visible images, adopting the same representation for the two types of images will result in the non-obvious thermal radiation target in the fused image, which can hardly be distinguished from the background. To solve the problem, a novel fusion algorithm based on nonlinear enhancement and non-subsampled shearlet transform (NSST) decomposition is proposed. Firstly, NSST is used to decompose the two source images into low- and high-frequency sub-bands. Then, the wavelet transform (WT) is used to decompose high-frequency sub-bands to obtain approximate sub-bands and directional detail sub-bands. The “average” fusion rule is performed for fusion for approximate sub-bands. And the “max-absolute” fusion rule is performed for fusion for directional detail sub-bands. The inverse WT is used to reconstruct the high-frequency sub-bands. To highlight the thermal radiation target, we construct a non-linear transform function to determine the fusion weight of low-frequency sub-bands, and whose parameters can be further adjusted to meet different fusion requirements. Finally, the inverse NSST is used to reconstruct the fused image. The experimental results show that the proposed method can simultaneously enhance the thermal target in infrared images and preserve the texture details in visible images, and which is competitive with or even superior to the state-of-the-art fusion methods in terms of both visual and quantitative evaluations.
Combining angiotensin receptor blockers with chlorthalidone or hydrochlorothiazide – which is the better alternative? A meta-analysis
Authors: Filipova Elena , Dineva Stela , Uzunova Katya , Pavlova Velichka , Kalinov Krassimir , Vekov Toni
Published: August 2020

Background

Hypertension is a disease with significant clinical and socio-economic consequences. The reduction in cardiovascular mortality and morbidity in patients treated for hypertension is directly related to the magnitude of blood pressure reduction. Diuretics have proven useful for the prevention of cardiovascular complications in addition to a long history of safety and efficacy. The main aim for this meta-analysis is to compare the efficacy of the combination of angiotensin receptor blocker (ARB) and chlorthalidone (CTLD) to the combination of ARB and hydrochlorothiazide (HCTZ) in patients with hypertension.

Methods

A comprehensive literature search was conducted through electronic databases PubMed, MEDLINE, Scopus, PsyInfo, Cochrane, eLIBRARY.ru, http://ClinicalTrials.gov and http://www.clinicaltrialsregister.eu in July 2020 to identify studies that investigate the effect of the combination of angiotensin receptor blocker with chlorthalidone or hydrochlorothiazide on the systolic and diastolic blood pressure in patients with hypertension. Changes in systolic and diastolic blood pressure (BP) expressed as a weighted mean difference (WMD) were our primary outcomes. The random-effects method was chosen as the primary analysis and results were presented with a 95% confidence interval (CI). Sensitivity analysis was performed and bias was assessed.

Results

Our search returned 2745 titles. Of them, 51 full-text articles remained to be subjected to assessment. Comparisons of ARB/HCTZ versus ARB showed changes in BP of −6.89 (−8.09, −5.69) mmHg for systolic BP and − 3.67 (−4.15, −3.19) mmHg for diastolic BP. For the ARB/CTLD versus ARB/HCTZ comparison changes were − 6.30 (−7.30, −5.29) mmHg for systolic BP and − 3.57 (−4.17, 2.98) mmHg for diastolic BP.

Conclusion

Our analysis suggests a small but significant favor for CTLD in blood pressure control when compared to HCTZ. We believe it should be considered as a valuable alternative for HCTZ and an option for fixed dose combinations with an ARB although further research is required.
Coexistence and extinction of a periodic stochastic predator–prey model with general functional response
Authors: Ji Weiming , Deng Meiling
Published: August 2020

This note deals with a stochastic predator–prey system with periodic coefficients and general functional response, and provides the threshold between coexistence and extinction. The result refines and evolves some prior investigations.
Body mass index and waist-to-hip ratio misclassification of overweight and obesity in Chinese military personnel
Authors: Zhu Qingqing , Huang Binbin , Li Qiaoli , Huang Liqian , Shu Wenbo , Xu Lin , Deng Qiongying , Ye Ziliang , Li Chunyan , Liu Peng
Published: August 2020

Background

The rising prevalence of obesity in military personnel has raised great concerns. Previous studies suggest that body mass index (BMI)- and waist-to-hip ratio (WHR)-based obesity classifications in US military personnel and firefighters have high false negative and subsequently cause obesity misclassification.

Objective

To determine whether BMI and WHR could reflect the fat mass of Chinese military personnel.

Methods

Three hundred fifty-three male Chinese military personnel and 380 age-matched male adults were recruited. Obesity classification was defined by BMI, WHR, and body fat percentage (BFP).

Results

Chinese military personnel had extremely low obesity rate determined by either BFP (0.3%) or BMI (0.6%). By combining overweight and obese individuals, BMI- and WHR-determined prevalence of overweight/obesity was 22.4% and 17.0% compared to BFP-based standard (4.0%) (P < 0.05). In reference to BFP, BMI and WHR have high false-positive rate compared to the control group. Further analysis showed that Chinese military personnel consisted of high percentage of BFPlowBMIhigh and/or BFPlowWHRhigh subpopulations. Eighty-one percent of BMIhigh and 78.3% of WHRhigh of them were BFP low.

Conclusions

Chinese military personnel has extremely low obesity rate. BMI and WHR have high false-positive rates in reference to BFP, which cannot accurately reflect the mass of adipose tissue and leads to obesity misclassification.
Risk estimation and prediction of the transmission of coronavirus disease-2019 (COVID-19) in the mainland of China excluding Hubei province
Authors: Wan Hui , Cui Jing-An , Yang Guo-Jing
Published: August 2020

Background

In December 2019, an outbreak of coronavirus disease (later named as COVID-19) was identified in Wuhan, China and, later on, detected in other parts of China. Our aim is to evaluate the effectiveness of the evolution of interventions and self-protection measures, estimate the risk of partial lifting control measures and predict the epidemic trend of the virus in the mainland of China excluding Hubei province based on the published data and a novel mathematical model.

Methods

A novel COVID-19 transmission dynamic model incorporating the intervention measures implemented in China is proposed. COVID-19 daily data of the mainland of China excluding Hubei province, including the cumulative confirmed cases, the cumulative deaths, newly confirmed cases and the cumulative recovered cases between 20 January and 3 March 2020, were archived from the National Health Commission of China (NHCC). We parameterize the model by using the Markov Chain Monte Carlo (MCMC) method and estimate the control reproduction number (Rc), as well as the effective daily reproduction ratio-Re(t), of the disease transmission in the mainland of China excluding Hubei province.

Results

The estimation outcomes indicate thatRcis 3.36 (95%CI: 3.20–3.64) andRe(t) has dropped below 1 since 31 January 2020, which implies that the containment strategies implemented by the Chinese government in the mainland of China are indeed effective and magnificently suppressed COVID-19 transmission. Moreover, our results show that relieving personal protection too early may lead to a prolonged disease transmission period and more people would be infected, and may even cause a second wave of epidemic or outbreaks. By calculating the effective reproduction ratio, we prove that the contact rate should be kept at least less than 30% of the normal level by April, 2020.

Conclusions

To ensure the pandemic ending rapidly, it is necessary to maintain the current integrated restrict interventions and self-protection measures, including travel restriction, quarantine of entry, contact tracing followed by quarantine and isolation and reduction of contact, like wearing masks, keeping social distance, etc. People should be fully aware of the real-time epidemic situation and keep sufficient personal protection until April. If all the above conditions are met, the outbreak is expected to be ended by April in the mainland of China apart from Hubei province.
Self-organizing topology for energy-efficient ad-hoc communication networks of mobile devices
Authors: Banerjee Indushree , Warnier Martijn , Brazier Frances M. T.
Published: August 2020

When physical communication network infrastructures fail, infrastructure-less communication networks such as mobile ad-hoc networks (MANET), can provide an alternative. This, however, requires MANETs to be adaptable to dynamic contexts characterized by the changing density and mobility of devices and availability of energy sources. To address this challenge, this paper proposes a decentralized context-adaptive topology control protocol. The protocol consists of three algorithms and uses preferential attachment based on the energy availability of devices to form a loop-free scale-free adaptive topology for an ad-hoc communication network. The proposed protocol has a number of advantages. First, it is adaptive to the environment, hence applicable in scenarios where the number of participating mobile devices and their availability of energy resources is always changing. Second, it is energy-efficient through changes in the topology. This means it can be flexibly combined with different routing protocols. Third, the protocol requires no changes on the hardware level. This means it can be implemented on all current phones, without any recalls or investments in hardware changes. The evaluation of the protocol in a simulated environment confirms the feasibility of creating and maintaining a self-adaptive ad-hoc communication network, consisting of multitudes of mobile devices for reliable communication in a dynamic context.
Prevalence of potential drug-drug interactions and associated factors among outpatients and inpatients in Ethiopian hospitals: a systematic review and meta-analysis of observational studies
Authors: Ayenew Wondim , Asmamaw Getahun , Issa Arebu
Published: August 2020

Background

Drug-drug interaction is an emerging threat to public health. Currently, there is an increase in comorbid disease, polypharmacy, and hospitalization in Ethiopia. Thus, the possibility of drug-drug interaction occurrence is high in hospitals. This study aims to summarize the prevalence of potential drug-drug interactions and associated factors in Ethiopian hospitals.

Methods

A literature search was performed by accessing legitimate databases in PubMed/MEDLINE, Google Scholar, and Research Gate for English-language publications. To fetch further related topics advanced search was also applied in Science Direct and HINARI databases. The search was conducted on August 3 to 25, 2019. All published articles available online until the day of data collection were considered. Outcome measures were analyzed with Open Meta Analyst and CMA version statistical software. Der Simonian and Laird’s random effect model, I2statistics, and Logit event rate were also performed.

Results

A total of 14 studies remained eligible for inclusion in systematic review and meta-analysis. From the included studies, around 8717 potential drug-drug interactions were found in 3259 peoples out of 5761 patients. The prevalence of patients with potential drug-drug interactions in Ethiopian hospitals was found to be 72.2% (95% confidence interval: 59.1, 85.3%). Based on severity, the prevalence of major, moderate, and minor potential drug-drug interaction was 25.1, 52.8, 16.9%, respectively, also 1.27% for contraindications. The factors associated with potential drug-drug interactions were related to patient characteristics such as polypharmacy, age, comorbid disease, and hospital stay.

Conclusions

There is a high prevalence of potential drug-drug interactions in Ethiopian hospitals. Polypharmacy, age, comorbid disease, and hospital stay were the risk factors associated with potential drug-drug interactions.
A study on the embarrassment of senders who missend emojis with opposite meanings on social apps: taking WeChat as an example
Authors: Liu Liyuan , Hsu Yen , Zhang Jie , Jiang Qianling
Published: August 2020

With the increasing popularity of social apps, sending emojis has become a very common way of expressing one’s emotions. However, situations often arise when people send the wrong emoji by mistake, or sometimes even an emoji with an opposite meaning, which can cause embarrassment to the sender. Taking WeChat as an example, which is widely used in Chinese communities, this study summarizes 10 types of dialogue situations in which the meaning of an emoji is wrongly sent and 12 types of emotional components that are related to embarrassment. The purpose of this study was to analyze the extent to which the 12 emotional components that are associated with embarrassment actually explain what embarrassment is, as well as the different degrees of embarrassment among the different genders and age groups. The results showed that (1) among the emotional components of embarrassment, shame has the highest explanation degree for embarrassment; (2) males are more likely to be affected by embarrassment than females; and (3) users aged 18–25 and 26–30 years are more likely to be affected by embarrassment than those aged between 31 and 40 when they mistakenly send WeChat emojis. This study provides a reference value for their sustainable psychological impact on social app users.
Detection of genetic variations in orobanche crenata using inter simple sequence repeat (ISSR) markers
Authors: Abdalla M. M. F. , Saleh Heba A. M. A. , Khater M. A.
Published: August 2020

Background

This recent investigation aimed to detect and characterize the genetic variabilities and genetic similarity in Orobanche crenata collected from naturally Orobanche-infested field at Gemmeiza Research Station, Agriculture Research Center (ARC), Egypt. Five different ISSR primers were used in this study.

Results

Obtained results showed that a huge genetic variation has been detected by these ISSR primers; moreover, there were clear relationship/genetic similarity between and within all collected O. crenata parasite plants. However, the results revealed that there were high relationships where similarity matrix ranged from 0.837 (the highest) between R4 and R17 followed by 0.831 for R4/R25 and in the end, the lowest one was R1/R29 similarity matrix 0.655.

Conclusions

It was noticed that the relationship and similarity did not reach 100% but the maximum was 83.7% (there were no identical plants); therefore, each Orobanche plant in this study was different genotype than neighboring plant within location.
Social stigmatisation among COVID-19 patients: addressing a potential source of COVID-19 transmission to healthcare staff in cardiac emergency and cardiac care units
Authors: Ali Farhan , Ali Sheikh Muhammad Ebad
Published: August 2020

During our routine work, we noticed an increased incidence of COVID-19 diagnoses among patients in the cardiac unit, which led to an exponential increase in COVID-19 cases among hospital staff. We found that patients hid their symptoms from the emergency doctors and attributed those symptoms to cardiac or other causes. Social stigmatisation appeared to be the root cause for hiding their symptoms. Hence, we recommended a strategy to introduce psychological counselling of patients who were suspected to be infected with COVID-19, with a normal cardiac workup to overcome social stigmatisation and save our general wards from COVID-19.
Impact of omission of completion axillary lymph node dissection (cALND) or axillary radiotherapy (ax RT) in breast cancer patients with micrometastases (pN1mi) or isolated tumor cells (pN0[i+]) in the sentinel lymph node (SN): Results from the MIRROR study
Authors: Tjan-Heijnen V. C. , Pepels M. J. , de Boer M. , Borm G. F. , van Dijck J. A. , van Deurzen C. H. , Adang E. M. , Menke-Pluymers M. B. , van Diest P. J. , Bult P.
Published: August 2020

CRA506

The full, final text of this abstract will be available in Part II of the 2009 ASCO Annual Meeting Proceedings, distributed onsite at the Meeting on May 30, 2009, and as a supplement to the June 20, 2009, issue of the Journal of Clinical Oncology.

No significant financial relationships to disclose.
Chemotherapy induces microssatelite instability (MIS) in plasma free DNA (pfDNA), peripheral blood mononuclear fraction (PBMNF) cells, and urine free DNA (ufDNA) of breast cancer (BC) patients as well as in normal PBMNF cells in vitro in the absence of amifostine (A)
Authors: Del Giglio A. , Pinto J. F. , Fonseca F. A. , Marsicano S. R. , Delgado P. O. , Coelho P. G. , Sant’Anna A. L. , Maeda P.
Published: August 2020

e11505

Background: We have previously shown that alkylating agent based chemotherapy regimens (AQT) could induce MIS in the PBMNF of BC patients in parallel to a decrease in the expression of the protein hMSH2 in these cells (Fonseca et al., 2005, Breast Cancer Res, 7, R28–32). Since plasma DNA derives mainly from tumor cells, we wanted to know if chemotherapy would also produce MIS in tumor DNA and if this phenomenon could be reproduced in vitro. Methods: 33 previously untreated female BC patients with a mean age of 51 years received AQT(16 ACT;3FAC;2 TAC;1FEC;10AC). Samples from 3 additional patients who received Fulvestrant only as neoadjuvant therapy were also included. Blood (pfDNA and PBMNNF) and urine (ufDNA) were evaluated at time 0,3 and 6 months with 6 MIS markers (BAT40,BAT26, MR2,TP53 PCR15.1, APC and ALU). Levels of fpDNA and fuDNA were measured by spectrophotometry. We incubated in vitro cultures of MCF- 7 cells and PBMNF cells with M at a dose of 0.7μg/ml for 30 minutes with and without A at 20% of the M dose and evaluated serially for 48 hours for MIS and hMH2 expression by immunohistochemistry. Results: We observed at least one MIS event in the PBMNF, fpDNA or fuDNA in 87%, 80% and 80% of the patients, respectively, mainly in BAT40 and BAT 26 markers. There was only 14.74% of concordance of MIS alterations between PBMNF and fpDNA and 8. 42% between fpDNA and fuDNA. Patients receiving Hormones also exhibited MIS. Interestingly, fpDNA levels increased significantly in patients with measurable disease who responded to therapy (47.4 ± 13.34 vs 14.37± 5.32; p = 0.021). In vitro, incubating MCF-7 cells and normal PBMNF cells with M ±A, we observed that we could induce MIS in both MCF-7 cells and normal PBMNF cells but A prevented MIS only in normal PBMNF cells. In normal PBMNF cells without A that sustained MIS there was a significantly decreased percentage of cells expressing hMSH2 ( 96% vs 57% p < 0.001). Conclusions: We conclude that Chemotherapy as well as Fulvestran can induce MIS in normal and malignant cells and that in vitro these effects could be reproduced by treatment with M and prevented in normal cells by A.

No significant financial relationships to disclose.
A phase I study assessing the feasibility and safety of intraductal pegylated liposomal doxorubicin (PLD) in women with breast cancer
Authors: Jacobs L. K. , Khouri N. , Jeter S. , Powers P. , Rudek M. , Gabrielson E. , Zhang Z. , Sukumar S. , Tsangaris T. , Stearns V.
Published: August 2020

e11506

Background: Most breast cancers originate in epithelial cells lining the breast ducts. Preclinical data suggest that intraductal administration of chemotherapy including PLD decrease tumor volume, prevent the development of new lesions, and eradicate pre-malignant disease. We initiated a clinical trial to determine the feasibility, safety, and maximum tolerated dose of PLD administered into one duct of women awaiting mastectomy. Methods: Women 18 or older awaiting mastectomy for breast cancer were eligible. Preoperative chemotherapy was allowed. T4 tumors, prior breast irradiation, or surgeries that may have altered the ductal system were excluded. Nipple aspiration and ductal cannulation were completed and the first 3 women received 5 mL of intraductal dextrose. PLD was administered to subsequent participants on a dose escalation schema based on preclinical pharmacokinetic and safety data. Serial doxorubicin (Dox) and doxorubicinol (Doxol) concentrations were determined in plasma by LC/MS/MS. At mastectomy (completed at least 2 weeks after intraductal administration of PLD), blue dye was injected into the treated duct and tissue was obtained for pharmacokinetic and biomarker analysis. Results: From 2/06 to 6/08, 14 women enrolled, and 12 underwent all study procedures. All dose levels up to 10 mg PLD per one duct were completed without serious adverse events. Median pain score was 0.9 (0–2.3). Intraductal PLD resulted in a dose-dependent increase in both systemic and local exposure to dox and doxol. Neither dox nor the metabolite was detected in the contralateral breast. Systemic exposure was lower than with conventionally administered PLD. Inflammatory changes were not observed on histopathological review of mastectomy specimens. Conclusions: We have established the logistics of intraductal administration of agents in an outpatient setting and it is feasible in women with and without prior chemotherapy. Biomarker data will be completed prior to the meeting. Future studies will evaluate other agents administered to one or more ducts.

[Table: see text]
Potential economic impact of the 21-gene expression panel according to tumor (T) size in lymph-node-negative (LNN), estrogen-receptor (ER)-positive early breast cancer (BC)
Authors: Prisco F. E. , Saad E. D. , Carvalho F. M. , Ojopi E. B. , Bacchi C. E.
Published: August 2020

e11518

Background: Use of the 21-gene panel may save costs in patients with LNN, ER-positive BC. Our previous analysis suggests that such would be the case in Brazil (SABCS 2008). However, the impact of the test may vary according to T size. Methods: Using a web-based survey with 30 (of a total of nearly 700) medical oncologists and literature data, we developed a model of direct medical expenses in two hypothetic cohorts (one without and one with access to the 21-gene panel) of Brazilian women with LNN, ER-positive BC, from the perspective of third-party payers. The questionnaire assessed patterns of care relating to chemotherapy (CT) regimens in each T size, type of premedication, use of G-CSF, and use of intravenous antibiotics for febrile neutropenia. Medication and 21-gene panel costs were the manufacturers’ recommended prices at the time of the survey. T size and recurrence score distributions followed those reported by Paik et al (NEJM 2004). CT use in the cohort with no access to the 21-gene panel was modeled according to the survey. In the cohort with access to the test, we assumed that patients with intermediate or high scores would receive CT, whereas patients with low score would not. Results: The table displays the number of patients receiving CT and the costs (CT, premedication, G-CSF, antibiotics, and the 21-gene panel) for two hypothetic cohorts of 100 patients. Conclusions: Our economic analysis suggests that the 21-gene panel overall would be cost-saving in Brazil, from the perspective of third-party payers. However, testing could actually increase direct medical costs in LNN, ER-positive T1 tumors, and decrease costs in T >2 cm.

[Table: see text]

[Table: see text]
Induction of primary systemic therapy by weekly paclitaxel: Predictive value of hormone receptors, HER-2, topoisomerase II- alpha, and other biological markers in relation to pathological complete response
Authors: Takao S. , Miyashita M. , Kohno N. , Wakita K. , Konishi M. , Kokufu I. , Yoshimura H. , Kasahara Y. , Kohno S. , Ienaga T.
Published: August 2020

e11525

Background: Randomized phase II study of epirubicin(E) plus cyclophosphamide (C) vs. weekly paclitaxel (P) as primary systemic therapy (PST) in stage II and III breast cancer(BC) have shown that there was no significant difference in the pathological complete response (pCR) rate between the EC and P groups (#568 ASCO 2008). The aim of this study is to evaluate the predictive value of hormone receptors, HER2, topoisomerase IIα(TOP II) and other biological markers in the EC and P groups as PST. Methods: Tissue samples were obtained before PST from pts who were randomized to either Arm A (EC: E 75 mg/m2 and C 600 mg/m2 every 3 W for 4 cycles) or Arm B (weekly P: P 80 mg/m2 weekly for 12 w). Pts received PST for 12 w, then underwent surgery. All pts received a crossover regimen as adjuvant chemotherapy.The pretreatment expression of estrogen receptor (ER), progesterone receptor(PgR), HER2, P53, Ki67, P21 and CD31 were analized by immunohistochemical staining. The status of TOP II gene was evaluated by FISH. Results: One-hundred- sixty pts (Arm A: n=82, Arm B: n=78 ) were estimable. The pCR rates were 13.4% in Arm A and 17.9% in Arm B(p=0.43). In both arms, pCR rate was significantly higher for pts whose tumors did not express ER nor PgR(ER/PgR-) compared with the receptor positive(ER/PgR+) pts. Pts with HER2 positive tumors tend to have higher pCR rate in Arm B compared with Arm A (32.2% vs. 12.5%;p=0.11). The pCR rate for pts with HER2 negative BC were not different in both Arms(A:14.0% vs. B:8.5%). Pts with triple negative (TN) (ER/PgR, HER2-) BC achieved almost same pCR in both Arms (A:25.0% vs. B:23.1%). However, the pCR rate for pts with nonTN BC was significantly higher in ArmB compared to Arm A (16.9% vs. 8.6%, p<0.001). The deletion and amplification of TOP II gene were not predictive of higher pCR rate to ArmA than to Arm B. The pretreatment expression of P53, Ki67, P21 and CD31 was unlikely to predict the higher response of any Arm. Conclusions: Althogh valuable predictive factor of pCR were not detected between EC and weekly P group, the efficacy of weekly P therapy as PST were equal to EC therapy regardless of HR,HER2 and TOP II gene status. Therefore, induction of PST by weekly P therapy seems to be promising.

No significant financial relationships to disclose.
Adjuvant paclitaxel, capecitabine, and trastuzumab for HER-positive breast cancer
Authors: Jouhadi H. , Benider A.
Published: August 2020

e11526

Background: Anthracyclines are integral components of most adjuvant chemotherapy regimens for surgically removed early breast cancer and are central to the accepted treatment standards. Recently the standard anthracycline regimen of doxorubicin plus cyclophosphamide was found to be inferior in preventing recurrence of breast cancer when compared to cyclophosphamide and docetaxel, questioning the necessity to expose patients to the potential cardiotoxicity of anthracycline in the adjuvant setting. Trastuzumab, cornerstone of treatment of breast cancers that overexpress HER2 produces Unfortunately, in combination with anthracyclines a high incidence of cardiotoxicity as seen in early trials of metastatic breast cancer. The trastuzumab adjuvant trial 006 from the Breast Cancer International Research Group shows for the first time that a nonanthracycline-containing regimen with trastuzumab has equivalent efficacy in decreasing the recurrence of breast cancer, with less incidence of cardiotoxicity when compared to anthracycline-containing trastuzumab adjuvant regimens. Methods: Our trial compared two adjuvant schemas of adjuvant chemotherapy arm1: paclitaxel(day 1-day 21: 6 courses), capecitabine(day1 to day 14: 6 courses) and trastuzumab (day 1 to day 21 for one year). Arm2: 4AC plus 4 TH plus trastuzumab for one year. Inclusion criteria: HER positive invasive ductal carcinoma, no lymphe node invaded at axillary dissection and no metatstasis, Negative ER and PR receptors Goal of study: evaluate efficacy and cardiac toxicity Results: From 2004 to 2005: 30 patient were included in each arm. After 3 years: DFS was respectively 93% in first arm and 90% in Second arm Four women developed severe cardiac toxicity in arm 2 versus no one in arm1 Conclusions: There is no difference in efficacy between the two arms but a significant increase in cardiac toxicity in the second arm.

No significant financial relationships to disclose.
Predictors of tumor shrinkage after anthracycline-based preoperative chemotherapy
Authors: Ermacora P. , Driol P. , Russo S. , Andreetta C. , Pisa F. E. , Alessi B. , Minisini A. M. , Mansutti M. , Fasola G. , Puglisi F.
Published: August 2020

e11531

Background: Anthracyclines are currently included in several chemotherapy (CT) regimens for the treatment of breast cancer (BC). However, increasing evidence suggests that benefit from these agents is limited to some subgroups of patients (pts). Aim of this study was to identify potential predictors of tumor shrinkage (TS) in a retrospective series of pts receiving preoperative anthracycline-based CT for operable BC. Methods: The study population consisted of 94 pts with large (>2 cm), any N, operable BC treated with preoperative anthracycline-based CT. Association between clinico-biological factors and clinico-radiological TS (by caliper and MRI) was assessed. TS was calculated as the difference between the maximum tumor diameter at baseline and the maximum tumor diameter after preoperative CT/ the maximum tumor diameter at baseline x 100. Immunohistochemical analyses for biological variables (ER, PgR, HER2, MIB1, topoisomerase II alpha) were performed on pretreatment biopsies. Results: In univariate analysis, the following variables were associated with clinical TS: high MIB-1 [Odd ratio (OR) 2.6, p = 0.03], type of taxane (docetaxel vs paclitaxel: OR 0.3, p = 0.01) and number of cycles of CT (> 4 vs ≤ 4: OR 9.2, p < 0.0001). In multivariate analysis, number of cycles of CT was the only independent predictor of clinical TS (OR = 9.2, p = 0.05). In univariate analysis, the following variables were associated with MRI TS: high MIB-1 (OR 2.4, p = 0.06), tumor size (≥ 40 mm vs < 40 mm: OR 5.6, p 0 0.01), taxane CT (yes vs no: OR 4.3, p = 0.02) and number of cycles of CT (> 4 vs ≤ 4: OR 4.4, p = 0.002). In multivariate analysis, high MIB-1 was the only independent predictor of MRI TS (OR = 3.7, p = 0.03). Conclusions: High MIB-1 expression and number of cycles of chemotherapy significantly predicted tumor shrinkage in patients treated with preoperative anthracycline-based chemotherapy. Further studies are warranted to better identify patients who derive benefit from anthracyclines.

No significant financial relationships to disclose.
The impact of residual cancer removed during subsequent surgeries on the outcome of patients with localized breast cancer
Authors: Kouzminova N. B. , Aggarwal A. , Aggarwal S. , Lin A. Y.
Published: August 2020

e11533

Background: A close or positive margin after breast cancer surgery is an important risk factor for local recurrence. A significant percentage of breast cancer patients need additional surgeries to obtain clear margins. This study evaluated the impact of residual cancer (RC) found upon subsequent operations on the outcome of the patients with localized breast cancer. Methods: Under IRB approved protocol, we retrospectively analyzed data on 573 patients with stage I-IIIA breast cancer treated at our institution during 1994–2004. 202 patients had complete tumor removal at single procedure with clear margins, 319 patients had subsequent surgery due to initially compromised margins and 52 patients with compromised margins did not have second surgery. Cox Proportional Hazard regression test was performed to evaluate the effect of RC found on subsequent surgery on distant recurrence (DR) and disease specific survival (DSS). Results: Median follow-up was 5.4 years. Among 319 patients who underwent second surgery, 57.7% did not have any RC; 13.1% had in situ RC and 29.2% had invasive RC. 12.9% (74/573) patients had DR. The risk of DR was higher in patients with RC found upon second surgery compared to those who had single procedure breast cancer removal (22.6% vs. 9.9%; HR 2.4, 95% CI 1.3–4.4, p=0.006). Similarly, finding of RC was a significant predictor of DSS (80.6% vs.92.6%; HR 2.9, 95% CI 1.4–5.7, p=0.003). Multivariate analysis revealed that tumor size above 5 cm, lymph nodes involvement and grade III were significant predictors of DR and DSS along with invasive RC found during subsequent surgeries. Delay in adjuvant chemotherapy due to need for subsequent surgeries strongly correlated with earlier DR in patients with invasive RC found on subsequent operations (rS = - 0.55, p = 0.019, two-tailed). Conclusions: Invasive residual carcinoma found during subsequent surgery after initial compromised margin is an important prognostic factor for DR and DSS, even after clear margins are eventually achieved.

No significant financial relationships to disclose.
Cost-effectiveness analysis of oncotype DX-guided treatment in early breast cancer
Authors: Tsoi D. T. , Inoue M. , Kelly C. M. , Verma S. , Pritchard K.
Published: August 2020

e11536

Background: Some early breast cancer patients with hormone receptor positive (HR+) disease may benefit from adjuvant chemotherapy in addition to hormonal therapy. Most guidelines recommend the addition of adjuvant chemotherapy for majority of women, leading to overtreatment causing considerable morbidity and cost. There has been recent incorporation of gene expression analysis to help aid in adjuvant chemotherapy decision making. We evaluated the cost-effectiveness of Oncotype DX-guided treatment as compared to treatment guided by Adjuvant! Online program. Methods: A Markov model was developed to compare the cost- effectiveness of treatment guided by either Oncotype DX or Adjuvant! Online in a cohort of 50-year-old women with HR+, lymph node negative breast cancer over a lifetime horizon. We assumed women assessed to be high risk all received chemotherapy followed by tamoxifen, and that those assessed to be low risk received tamoxifen only. The model took a health care payer's perspective with results reported in 2008 Canadian dollars ($). Event rates, costs and utilities were derived from the literature. Both costs and benefits were discounted at 5%. Sensitivity analysis for key parameters in the model was conducted. Outcome measures were life year gained, quality- adjusted life years (QALYs), lifetime costs, and incremental cost-effectiveness ratios (ICERs). Results: For a 50-year-old woman, Oncotype DX-guided treatment was associated with an incremental lifetime cost of $4,200 and a gain in 0.067 QALY, with an ICER of $61,800/QALY compared with treatment guided by Adjuvant! ICER was positively correlated to the cost of Oncotype DX and the age of patients. Results were most sensitive to probabilities relating to risk categorization and recurrence rate. Conclusions: Relative to Adjuvant!-guided treatment, Oncotype DX-guided treatment appears cost-effective with an ICER of $61,800/QALY from a Canadian health care perspective.

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