bluuebunny/crossref_metadata_2025_split huggingface dataset:
Frameworks for health systems performance assessment: how comprehensive is Ghana’s holistic assessment tool?
Authors: Kumah Emmanuel , Ankomah Samuel E. , Fusheini Adam , Sarpong Emmanuel Kusi , Anyimadu Eric , Quist Ato , Koomson Brian 
Published: March 2020

Abstract
Background
Measuring the performance of a health system is an essential requirement in creating systems that generate efficient, equitable, patient-focused, accessible and sustainable results. A fundamental requirement for a performance measurement system is the development of an assessment framework within which specific performance measures could be defined and applied regularly. This paper examines the comprehensiveness of Ghana’s health system assessment framework called the Holistic Assessment Tool in relation to some of the internationally recognized frameworks. The paper also analyzes trends in the performance of the health system to understand whether or not an improvement has been recorded following the adoption and implementation of the Holistic Assessment Tool.

Methods
Mainly secondary data were used in this analysis. Searches were conducted on Google Scholar, PubMed, Scopus and Science Direct between May and July, 2019 for published documents on health system performance assessment. We also obtained unpublished documents from Ghana’s Ministry of Health, Ghana Health Service website, and Ghana Statistical Service database. Descriptive statistics were used to examine trends in the performance of the Ghanaian health system.

Results
While the tool provides a national framework for evaluating the performance of the Ghana Health system in several domains, the Holistic Assessment Tool does not cover key health system domains such as information systems for health, access to essential medicines, and patient-centeredness. Also, the scope of the assessment program seems limited to the evaluation of the Ministry of Health’s annual plans, programs and projects. However, the health system has recorded improvements in population health indicators, such as life expectancy at birth, infant mortality, under-5 mortality, HIV prevalence and disease burden (in terms of disability adjusted life years).

Conclusions
The Holistic Assessment Tool is a useful framework, but needs further refinement, both in scope and in conceptual robustness. Future studies should consider exploring factors influencing performance of the Ghanaian health system. Such information will help in strategizing for better and more improvements.
Nucleotide excision repair polymorphisms modulate overall lung cancer survival and responsiveness to platinum based chemotherapy agents
Authors: Matakidou A. , Eisen T. , Bridle H. , Houlston R. S. 
Published: March 2020

10004 Background: The role of DNA repair in maintaining genomic stability and its role in modulating response to chemotherapy agents raises the possibility that variation in these genes may affect lung cancer prognosis. Methods: To comprehensively evaluate the impact of variation in the nucleotide excision repair (NER) pathway on lung cancer prognosis, we analysed 408 lung cancer patients for all coding, non-synonymous single nucleotide polymorphisms (SNPs) within NER-related genes. Results: Mean age of lung cancer diagnosis among patients was 63 years, 105 patients with small cell lung cancer (SCLC) and 299 with non-small cell lung cancer (NSCLC). The mean follow-up time was 24 months and a total of 234 deaths were observed. Mean survival time was 17.3 and 18.6 months for SCLC and NSCLC respectively. The XPG H1104D minor allele homozygote and the tightly linked CSB M1097V, R1213G, and Q1413R heterozygote genotypes were associated with decreased overall survival, irrespective of whether patients were treated with or without platinum chemotherapy (HRs of 2.22, 95% CI: 1.19–4.16; p=0.013 and 1.39, 95% CI: 1.05–1.84; p=0.02 respectively). No statistically significant interaction was detected between the at-risk genotypes and histology and/or stage of disease at diagnosis. To assess the predictive value of these SNPs in relation to platinum based chemotherapy, genotype-survival associations were evaluated in non-platinum and platinum treated patients. In non-platinum treated patients the RAD23B A249V and CSB M1097V minor allele genotypes were associated with decreased overall survival (p=0.004 and 0.002 respectively), whilst the XPC K939Q minor allele genotype was predictive of improved survival (p=0.03). In platinum-treated patients, carriers of the XPG H1104D minor allele were found to have a statistically significant decrease in their overall survival (p=0.04 and 0.004 for minor allele heterozygote and homozygote patients respectively). Conclusions: These findings suggest that genetic polymorphisms in the NER genes may modulate overall lung cancer prognosis as well as response to platinum-based chemotherapy agents, independent of histological diagnosis and stage of disease at presentation. No significant financial relationships to disclose.
Analysis of genomic DNA copy number alterations in chromosome arm 18q demonstrates distinct molecular categories of colorectal carcinoma
Authors: Ji H. , Zhang M. , Farnam K. , Salari K. , Davis R. , Ford J. M. 
Published: March 2020

10005 Background: Genomic instability is a major feature of neoplastic development in colorectal carcinoma and other cancers. Specific genomic instability events such as genomic deletions have potential utility as biologically relevant prognostic biomarkers. Loss of heterozygosity (LOH) on chromosome arm 18q is an indicator of colorectal carcinoma behavior and potentially, prognosis. For stage II and III colorectal cancer, a number of retrospective studies have shown strong correlations between deletions in 18q and reduced survival. However, other studies have failed to identify this correlation. This discrepancy is likely the result of different sets of genetic markers and their widely disparate locations along chromosome arm 18q, often separated by megabases. New technologies are needed to overcome these issues. Methods: Using a novel genomic technology called molecular inversion probes (MIPs), we analyzed genomic deletions at exon-level resolution in primary colorectal carcinoma. Unlike microsatellite genetic markers, MIPs are not dependent on having informative alleles to discern a LOH event. This enables querying microsatellite genetic markers used in any clinical study. We designed a set of probes to interrogate several hundred individual exons of over two hundred cancer genes with an overall distribution covering all chromosome arms. Also represented were a series of over 100 probes along chromosome arm 18q representing genetic markers used in clinical studies. An analysis was carried out on primary tumor samples from patients with stage II and III disease. Results: We discovered several distinct categories of colorectal carcinomas based upon their profile of 18q genomic deletions and other allelic imbalances. Colorectal carcinoma extent of invasion showed an association with cluster designation which suggests that the multiple genomic instability events influence the invasive behavior of colorectal carcinoma. Conclusions: Colorectal cancer has distinct patterns of 18q genomic deletions, representing a potential molecular classifier. This finding has potential clinical ramifications given the application of 18q LOH events as an indicator for adjuvant treatment in stage II colorectal carcinoma. No significant financial relationships to disclose.
Phase II breast cancer chemoprevention trial of the third generation selective estrogen receptor modulator arzoxifene
Authors: Fabian C. J. , Kimler B. F. , Anderson J. R. , Chamberlain C. , Mayo M. S. , Zalles C. M. , O’Shaughnessy J. A. , Lynch H. T. , Johnson K. A. , Browne D. 
Published: March 2020

1001 Background: Arzoxifene (ARZ) is a third generation SERM with efficacy in metastatic breast cancer but lacking uterine agonist activity. Methods: We conducted a randomized, double-blind, placebo-controlled Phase II prevention trial in 199 high risk women assessing the effects of ARZ 20 mg/day on several risk biomarkers. Biomarkers, including cytomorphology of breast epithelial cells obtained by random periareolar FNA (RPFNA) were assessed at baseline and following 6 months of placebo or ARZ. Subjects were stratified by presence or absence of atypia, ER expression, BRCA1/2 mutation, as well as menopause status. Results: At entry, mean age was 47, 52% were premenopausal and 47% of postmenopausal women were taking HRT. Mean 10 year Gail was 6.8% and mean Masood cytology index score was 14.3. The ARZ and placebo groups were well matched. The protocol defined primary endpoint was a decrease in RPFNA cytology Masood index score by ≥3 points at 6 months and required 160 evaluable subjects for 81% power to detect a change from 30% to 52% of subjects showing improvement. For the 181 evaluable subjects, there was no significant difference in the proportion of women achieving ≥3 point improvement (19% placebo vs. 24% ARZ, p=0.46); or in change in mean index score (0.6 placebo vs. 0.9 ARZ, p=0.53). There was also no difference in grade 3 or 4 side effects or dropout prior to 6 months. However, comparing ARZ to placebo, there was favorable modulation of the two risk biomarkers, mammographic breast density (p=0.001) and IGF-1:IGFBP-3 ratio (p=0.001), and reduction in bone turnover biomarker osteocalcin (p= 0.002), but without an increase in endometrial thickness. Conclusions: Although improvement in cytomorphology after 6 months of ARZ was not shown, the acceptable side effect profile and favorable modulation of other biomarkers (breast density, IGF-1:IGFBP-3, osteocalcin) provides support for continued evaluation of ARZ as a breast cancer prevention agent. No significant financial relationships to disclose.
Case control study of hormone replacement therapy (HRT) and breast cancer in Japanese women
Authors: Takeuchi M. , Saeki T. , Sano M. , Sonoo H. , Honjo H. , Ochiai K. , Sugano H. , Komiike Y. 
Published: March 2020

10012 Background: Some prospective studies in US and UK (represented by Women’s Health Initiative and Million Women Study) show that HRT use may increase the risk of breast cancer. However, it is unclear whether or not this perspective is applicable to Japanese women, due to several factors such as the difference in incidence of breast cancer, difference in HRT prevalence, which are to be concerned in this study. To investigate the relationship between HRT use and breast cancer, a case-control study was conducted in Japan. Methods: We sent self-administered questionnaire to 4,500 cases who have a previous history of confirmed histological breast cancer and 4,500 controls who were selected according to the inclusion criteria. All the subjects were between age 45 and 69 at the time of enrollment. Among these subjects, 3,434 in case group and 2,427 in control group sent back their questionnaire (total 5,861). The datacenter was run in Kitasato Univ. and the statistical analysis was performed using SAS (version 9.1). Control was selected by considering the screening record for GI disease and respiratory disorders, with no previous history of breast cancer, gynecological and hormonal disease at the time of screening. We asked about past history of exposure to the factors supposed to be breast cancer-causing; previous or current use of HRT, age at diagnosis, academic background, BMI, lifestyle habits, age of menarche, birth history, history of breast feeding, family history, use of contraceptive agents and menopausal status. Results: As the main analysis result, 164 (5.0%) out of 3,316 cases and 253 (7.4%) out of 2355 controls had used HRT (Odds ratio 0.432 [95% CI 0.352–0.530]. Conclusions: The result of this study shows that HRT users were less likely to develop breast cancer than never users. However, in this study, there was a difference in the observation period for the past use of HRT between cases and controls. Considering the transition of HRT prevalence in Japan, there may be a possibility that this difference can be a cause of a serious bias for the main analysis result. Further sensitivity analyses are needed to evaluate the robustness of the findings and this point is under consideration. No significant financial relationships to disclose.
PTEN activity could be a predictive marker of trastuzumab efficacy in the treatment of ErbB2-overexpressing breast cancer
Authors: Fujita T. , Kawasaki K. , Takabatake D. , Takahashi H. , Ogasawara Y. , Doihara H. 
Published: March 2020

10026 Background: Trastuzumab is the only HER2/neu-directed therapy for the treatment of patients with metastatic breast cancer. The efficacy of trastuzumab depends on the HER2/neu status of the tumor and the patient’s prior treatment, but even when patients are selected on the basis of HER2/neu gene amplification, the single-agent response rate ranges from 12 to 30% and few patients respond to trastuzumab monotherapy. Here we propose PTEN as a predictive biomarker for trastuzumab efficacy. Methods: Human breast cancer SKBR3 and drug-resistant SKBR3/R cells were analyzed, in vitro. Also we examined, retrospectively, clinical samples from patients who had been treated with trastuzumab for the metastatic disease and analyzed the relationship between trastuzumab efficacy and PTEN expression profile with immunihistochemistry. The PTEN expression level was scored semiquantitatively based on staining intensity and distribution using the immunoreactive score. Statistical analysis was performed using the two-tailed student’s t test, Fisher’s test and ANOVA. Results: The PI3K/Akt signaling pathway was observed to be highly active in the drug-resistant cells, and their level of PTEN was significanctly low compared with parental SKBR3 cells. Delivery of antisense PTEN duplex siRNA significantly decreased the trastuzumab chemosensitivity of parental SKBR3 cells, and marked activation of Akt signaling pathway was also recognized in oligonucleotid delivered parental cells. Moreover, in clinical analysis, immunohistochemical investigation revealed that trastuzumab treatment was remarkably successful in patients with elevated PTEN expression and statistically significant (p<0.05). Conclusions: PTEN activity might play an important and major role in its HER2/PI3K/Akt-mediated anti-tumor effect, and could be a useful biomarker for predicting the efficacy of trastuzumab in the treatment of breast cancer. No significant financial relationships to disclose.
Oropharyngeal squamous cell cancers (OSCC) bearing transcriptionally active human papillomavirus (HPV) display distinct protein expression profile
Authors: Weinberger P. , Kountourakis P. , Sasaki C. , Haffty B. , Camp R. , Rimm D. , Psyrri A. 
Published: March 2020

10028 Background: It is known that among HPV DNA+ OSCCs only the transcriptionally active ones are biologically and clinically relevant. pRb downregulation by HPVE7 results in p16 upregulation. We previously showed (JCO, Feb 2006) that p16 expression defines transcriptionally active HPV+ tumors. Thus, OSCC tumors can be Class I: HPV−/p16−, Class II: HPV+/p16−, or Class III: HPV+/p16+. We hypothesized that tumors classified by these criteria would show different protein expression profiles. Methods: Following institutional review board approval, paraffin-embedded specimens from 77 patients were collected from Yale-New Haven Hospital archives. Patients with OSCC treated with radiotherapy (RT) or surgery and RT were eligible. We used real-time polymerase chain reaction for HPV 16 and immunohistochemistry for p16 protein expression to classify 77 patients with OSCC. Tumors were classified into a 3-class model based on p16 expression and HPV DNA presence: Class I (HPV−, p16−) Class II (HPV+, p16−) and Class III (HPV+, p16+). A tissue microarray including these cases was constructed and examined for 13 target proteins with known involvement in tumor suppression or progression. We used a method of in-situ automated quantitative protein expression analysis (AQUA). Protein signal (AQUA score) was scored on a scale of 0–255.Protein expression between groups was analyzed by analysis of variance (ANOVA). Results: Thirty tumors were class I (39%), 29 were class II (38%), and 18 were class III (23%). There were significant differences for protein expression of Met (p=0.005), β-catenin (p=0.009), pRb (p=0.001), p53(p=0.026), epidermal growth factor receptor (EGFR) (p=0.009) and Vascular Endothelial Growth Factor (VEGF) (p=0.028). There was no difference for ki-67, COX2, p27, p21 or Cyclin D1 expression, while ERK2 and p14 trended towards significance (p=0.09 and 0.054, respectively). Conclusions: We demonstrated that tumors classified by HPV DNA presence and p16 expression status have different molecular phenotypes. Of particular note, class III tumors demonstrated increased expression of Met, β-catenin, EGFR and VEGF. These findings may prove useful for patient selection for molecular-targeted therapies. [Table: see text]
Detection of novel variant TMPRSS2 /ERG fusion transcripts suggests independent genomic alterations may underlie origin of multi-centric prostate cancer
Authors: Yoshimoto M. , Joshua A. M. , Chilton-Macneill S. , Bayani J. , Prasad M. , Fleshner N. , Finelli A. , Evans A. , Sweet J. , Squire J. , Zielenska M. 
Published: March 2020

10029 Background: Most of the early successes in identifying chromosomal translocations in neoplasias came from the study of hematological malignancies and sarcomas, with limited evidence that consistent genomic rearrangements were present in epithelial malignancies. Recently it was reported that ∼75% of prostate cancers carry a genomic rearrangement leading to fusion of the TMPRSS2 locus to either the ERG or ETV1 genes (both ETS transcription factors). In the fusion gene, the androgen-sensitive promoter elements of TMPRSS2 are thought to mediate over-expression of these ETS transcription factors. Over-activity of the ETS family of transcription factors has been suggested to be involved in the transition from pre-neoplasia to carcinoma as they regulate genes involved in processes such as adhesion, motility, invasion and angiogenesis. Methods: Using both RT-PCR and FISH with published primers and BACs respectively we analyzed 15 samples of prostatic carcinoma from radical prostatectomies and sequenced a subset of the TMPRSS2/ERG fusions. Results: We have found ERG-TMPRSS2 fusion transcripts in 6 samples and no ETV1-TMPRSS2 fusions. Of the 6 fusion tumours, 5 were Gleason 7 and 1 was Gleason 9. Tumour stages ranged from T2a-T3b. One sample with multi-centric carcinoma exhibited 2 distinct in-frame rearrangements generating novel TMPRSS2 /ERG fusion transcripts. Variant I TMPRSS2/ERG transcript was 430 bp and it led to fusion of exons 1 and 2 of the TMPRSS2 gene with exons 5 and 6 of the ERG gene. Variant II TMPRSS2/ERG fusion transcript was slightly smaller at 350 bp and it led to fusion of exon 1 of the TMPRSS2 gene to exons 5 and 6 of the ERG gene. These novel transcripts appear to be smaller than the published fusion proteins but preliminary analysis suggests that all known regulatory and functional protein domains are maintained. Conclusions: The demonstration of two new TMPRSS2/ERG variant fusion transcripts in prostate cancer deserves further study to evaluate their functional impact and prognostic and pathological importance. Moreover the presence of two distinct transcripts within a single multi-centric tumor provides genomic evidence that independent clonal neoplasms can arise synchronously in prostate cancer. No significant financial relationships to disclose.
Comparison of genomic changes between tumors detected by screening mammography versus other methods
Authors: Becker T. E. , Ellsworth R. E. , Ellsworth D. L. , Deyarmin B. , Hooke J. A. , Shriver C. D. 
Published: March 2020

10033 Background: The prognosis in patients with breast cancer detected by screening mammography has been found to be significantly better than those with similar-sized tumors detected by other methods (e.g. physical examination). (Joensuu, et al. 2004). Given the similar pathological characteristics, outcome differences may be explained by molecular differences within the tumors. To address this question, the relationship between genomic instability and methods of detection was assessed using allelic imbalance (AI) in similarly sized primary breast tumors from patients with breast cancer identified by screening mammography versus other methods. Methods: Patients with stage I breast cancer identified by screening mammography (n=50) versus other methods (n=50) were selected. Samples were matched between the two groups for clinical information. DNA was extracted from pure populations of tumor cells obtained by laser microdissection. Referent DNA was obtained from blood or disease-free skin samples from each patient. A panel of 52 microsatellite markers from 26 chromosomal regions commonly altered in breast cancer was used to assess AI, determined by the peak height ratio (≤0.35) between alleles from tumor and referent samples. Fisher’s exact test and Student’s t-tests were used to test for significant differences in levels of AI. Results: When clinical parameters such as age, ethnicity, menopause and status of tumor hormone receptors or HER2 were examined between tumor groups, no significant differences were detected. The overall frequency of AI between tumors detected by screening mammography (21.8%) versus other methods (22.3%) was similar (P=0.93). When patterns of AI were examined, none of the 26 chromosomal regions detected here showed a significant difference in AI events between the two groups. Conclusions: In this study, we have shown that global chromosomal differences are likely not the cause for the difference in tumor detection and prognosis between patients whose tumors were detected mammographically versus those whose were not. Prognostic factors known to correlate with disease aggressiveness and recurrence (e.g. hormone receptor or HER2 status) were also shown to not be associated with this difference in tumor detection among our patients. No significant financial relationships to disclose.