bluuebunny/crossref_metadata_2025 huggingface dataset:
Altruism and Structure of Values: An Experimental Investigation
Authors: Gandullia Luca , Lezzi Emanuela , Parciasepe Paolo , Siri Lidia
Published: March 2020

Individual structure of values explains many behaviours that people consciously undertake when setting goals for themselves, both in personal and social dimensions. Altruistic behaviours may be influenced, for example, by personal concerns for the well-being and interests of others that fit into a broader framework of values. We use an online experiment to explore how donors (pure altruists, warm-glow givers and impure altruists) differ in their structure of values, and whether their prosocial behaviours are guided by specific sets of values and motivations. We find that donors give great importance to the relationship with others, and they identify themselves with the norms and attitude of a community, responding to the values of tradition, conformity, benevolence and universalism. On the contrary, non-donors do not seem to have this kind of values reference and, therefore, are not inclined to make a donation. Furthermore, we find that impure altruists wish to achieve self-enhancement objectives through altruistic behaviour, as pure warm-glow givers do, but, at the same time, they make a donation because it represents a genuine altruistic act, similarly to pure altruists.

JEL: H41, C90, C91
Turning Straw to Gold: Mobilising Symmetry in Responsible Research and Innovation
Authors: Mamidipudi Annapurna , Frahm Nina
Published: March 2020

This article aims to reflect on the role of Science, Technology and Society (STS) research(ers) in co-constructing Responsible Research and Innovation (RRI) in the Global South. By reporting on RRI research in the Global South, here the Indo-Dutch NWO-MVI project on rice straw burning in Punjab, we make an argument for approaching RRI as a symmetric process of knowledge production mobilised by local actors and researchers alike. For STS researchers to responsibly engage with local innovation systems, their activities need to go beyond knowledge provision and towards facilitating the ownership and circulation of local meanings and means to responsibly innovate. Rather than understanding RRI as a fixed framework to govern innovation practices, this article reflects on RRI as an approach that combines research with intervention. We propose that following the principle of symmetry can turn RRI into a productive tool for the mobilisation of embedded local principles that can organise innovation systems in a responsible way. In particular, symmetry allows the re-location of meanings and practices of innovation as well as the re-negotiation of multiple notions of responsible governance.
Do Women’s Advancement and Gender Parity Promote Economic Growth? Evidence from 30 Asian Countries
Authors: Mishra P. K. , Mishra S. K. , Sarangi M. K.
Published: March 2020

Women’s advancement and consequential gender equality have significant implications for human capital formation, increase in labour productivity, employment creation, poverty reduction, and overall socio-economic and human development. So, inclusive growth and sustainable development would not be possible without women’s empowerment and gender equality. Thus, targeting women’s empowerment is extensively relevant for Asian countries. In this context, this article explored the impact of the gender factors on the economic growth of 30 Asian economies over the period from 1997 to 2015 by using panel autoregressive distributive lag (ARDL) model. It provides the evidence of an overall positive impact of the gender parity index of health, education, employment and democratic representation on the economic growth of Asia in the long run. Therefore, gender equality is an important determinant of economic growth in Asian countries, and hence, should be on board while planning for the empowerment of women.
Application of Systems Thinking to Dent Child Malnutrition: A Palghar District, India Case Study
Authors: Jain Rahi , Narnaware Prashant
Published: March 2020

Child malnutrition is an important low-and middle-income country (LMIC) issue influenced by biological and socio-economic factors. The solution is dependent on the stakeholders and interactions between them. The multidimensionality and context-dependency of causative factors make system thinking-based approach, namely network analysis, an effective tool to map the decision-making on countering child malnutrition. The study used Palghar district, India, as a case study to perform the stakeholder network analysis for identifying the various stakeholders who were targeted by actions and initiatives of district administration. The network analysis was performed for three temporal phases, namely Phase I (pre-2014), Phase II (years 2014–2017) and Phase III (2017 onwards). The study found that both network density of the system and child nutrition status have increased temporally. The study found an increase in network density due to an increase in the number of stakeholder groups targeted, implementation of new actions/initiatives and expansion of existing actions/initiatives to other stakeholders. A significant increase in focus towards the stakeholders influencing the socio-economic environment of the child is found in Phase III as compared to Phase II. Further, the study found that family and elite group have started featuring as prominent stakeholder targets for various actions. The study concludes that a greater incorporation of system-thinking approach in decision-making could help in effectively addressing child malnutrition and similar healthcare issues.
Social Innovation for Agricultural Development: A Study of System of Rice Intensification in Bihar, India
Authors: Kumar Vikas
Published: March 2020

The social innovation inclines to an emphasis on ‘systems and processes of change in social relations’ and ‘innovation is a new idea, product or process that addresses social and environmental challenges and their needs’. It is newly growing up as a field of practice that is done by people. It has occurred from the broader field of innovation studies. In this article, the System of Rice Intensification (SRI) has been taken as a case of social innovation, which helps to increase the productivity of rice and enhance the income of the farmers. The literature related to SRI suggested that the technique is sustainable and innovative because of the less use of inputs and changes in some set of principles (i.e., planting, fertilizer, water and seeds) whereas increasing output in terms of production and productivity of the crop. In this sense, aim of the article is to evaluate the impact of the SRI technique within the framework of social innovation in Patna district, Bihar, India. In a wider context, the question is not about whether it is intensifying or not, rather emphasis should be on how farmers deal with changing environmental and socio-economic factors. Moreover, there is a need to delve deeper into implantation strategies in the local context and evaluate their impact in terms of opportunities and constraints during adaptation. In addition to this, an exploratory research design was followed to study SRI. Criterion and expert sampling were employed to select the farmers, and data were collected by a personal interview method with the help of a structured schedule. However, the data indicate the production and productivity of paddy are increased through SRI, but variation exists among different blocks of the district. It is clearly evident from the data that nearly 42 per cent of farmers from all blocks have witnessed an increase in food sufficiency. In the case of income due to the sale of excess produce is 57 per cent.
Lessons learned from community- and home-based physical activity programs: A narrative review of factors influencing women’s participation in cardiac rehabilitation
Authors: Vidal-Almela Sol , Czajkowski Brenna , Prince Stephanie A , Chirico Daniele , Way Kimberley L , Pipe Andrew L , Reed Jennifer L
Published: March 2020

Background

Cardiovascular disease remains a leading cause of death in women. Despite the well-known benefits of cardiac rehabilitation, it remains underutilized, especially among women. Physical activity programs in the community, however, attract a large female population, suggesting that they overcome barriers to physical activity encountered by women. The characteristics of interventions that extend beyond the traditional cardiac rehabilitation model and promote physical activity merit examination.

Objectives

This narrative review aimed to: (a) summarize women’s barriers to attend cardiac rehabilitation; (b) examine the characteristics of community- and home-based physical activity or lifestyle coaching interventions; and (c) discuss which barriers may be addressed by these alternative programs.

Methods

Studies were included if they: (a) were published within the past 10 years; (b) included ≥70% women with a mean age ≥45 years; (c) implemented a community- or home-based physical activity intervention or a lifestyle education/behavioral coaching program; and (d) aimed to improve physical activity levels or physical function.

Results

Most interventions reported high (≥70%) participation rates and significant increases in physical activity levels at follow-up; some improved physical function and/or cardiovascular disease risk factors. Community- and home-based interventions address women’s cardiac rehabilitation barriers by: implementing appealing modes of physical activity (e.g. dancing, group-walking, technology-based balance exercises); adapting the program to meet participants’ needs; offering flexible options regarding timing and setting (e.g. closer to home, the workplace or faith-based institutions); and promoting social interactions.

Conclusion

Cardiac rehabilitation can be enhanced by understanding the specific needs of women; novel elements such as program offerings, convenient settings and opportunities for socialization should be considered when designing cardiac rehabilitation programs.
Perceptions of Stakeholders on the ‘Redraftability’ of Construction Contracts
Authors: Jagannathan Murali , Delhi Venkata Santosh Kumar
Published: March 2020

Disputes in construction projects have become an integral part of the construction process. In addition to reducing their productivity, disputes create mistrust between the involved parties. A variety of reasons that contribute to the occurrence of disputes in construction projects have been discussed in the literature. One among them is the nature of the construction contract that exists between the parties. A review of the existing literature brings to the fore two schools of thought regarding the drafting of construction contracts. While the traditional school considers the contract as those documents that contain inherent incompleteness and hence prone to disputes, the liberal school believes that construction contracts can be drafted in an efficient manner to prevent disputes. In this exploratory research, we conducted semi-structured open-ended interviews with experts in contractual decision making and contract drafting in construction organizations to understand their perspective on contract drafting/redrafting process and to classify them under the respective school of thought. The study reveals some interesting insights about the perceptions and motivations of the contract drafters and the senior management of construction organizations in India, when it comes to drafting dispute-free equitable contract documents. We believe that the findings of our study will pave the way for further research in drafting efficient construction contracts that can be practicable and dispute-resistant in the Indian context.
Trajectories of Women’s Property Rights in India: A Reading of the Hindu Code Bill
Authors: Rajak Komal
Published: March 2020

The right to property is especially sacrosanct since the state of financial deficit renders women’s condition very much pathetic in a patriarchal society. In order to get a clear picture of women’s property rights in a caste based patriarchal society like India, here, the Hindu Code Bill is taken into consideration as a major plot because the bill has a history of egalitarian dialogue and had been initiated as an effort to make an egalitarian structure, wherein women would be enjoying property rights as equal to men. This article deals with the trajectories of women’s property rights in India after the introduction of the Hindu Code Bill. So, the focus area of the study is on women’s rights in ancient Indian laws and their development in modern laws since the colonial period to the Hindu Code Bill.
Tibial access for supra-inguinal embolization in extremely obese patients
Authors: Smith Jason C. , Cho Alex L. , Fujimoto Scott T.
Published: March 2020

Extreme obesity is a risk factor for hemorrhagic complications of femoral access (FA). Femoral lines, hematomas, pelvic binders and coagulopathy in the trauma scenario may also add difficulty and/or risk to FA. Radial access (RA) for routine peripheral endovascular procedures has been popularized owing to decreased hemorrhagic complications, increased patient satisfaction, and decreased operator radiation dose. However, though uncommon, cerebrovascular complications from RA approach are a known risk. Relatively recently, tibial access (TA) has been used for lower extremity peripheral vascular disease interventions. The advantages of TA mirror that of RA, with few and mostly minor complications, and the risk of iatrogenic cerebral embolization is nil. We report the feasibility of TA for supra-inguinal embolization in two extremely obese patients {body mass index > 40 kg/m2} following motor vehicle accidents. Commercially available base and microcatheters were used to perform embolization of the affected lower abdominal or pelvic arteries in standard fashion via a novel trans-tibial artery approach.
RTOG 9804: A prospective randomized trial for “good risk” ductal carcinoma in situ (DCIS), comparing radiation (RT) to observation (OBS)
Authors: McCormick Beryl
Published: March 2020

1004

Background: Whole breast RT following conservation surgery (BCS) for low risk DCIS has remained controversial despite several large trials comparing RT to OBS, all showing significant benefit in local control with RT. RTOG 9804 compares RT to OBS for mammographically detected disease, of low or intermediate nuclear grade, <2.5 cm size, and surgical margins ≥ 3 mm. Tamoxifen (TAM) use for 5 years was allowed but not required. Methods: The primary endpoint was ipsilateral breast local failure (LF). LF and contralateral breast failures (CBF) were estimated by the cumulative incidence method and treatment arms compared by log-rank test. Disease-free (DFS) and overall survival (OS) were estimated by the Kaplan-Meier method and treatment arms compared by log-rank test. Patients were stratified by age, margin width, grade, TAM use, and primary size. With 1790 patients, 80% power and using a 2-sided log rank test at 0.05, the study was designed to detect a reduction in 5-year local recurrence from 6% to 3.5% with RT. Results: Accrual goals for the planned 1790 patients were not met; the study was closed early. From December 1999 to July 2006, 636 women were randomized to receive 50 Gy in 5 weeks vs. OBS. 43 women were ineligible on review and 8 withdrew consent. Median follow-up (F/U) time was 6.46 years. Mean age was 59; TAM was used in 62% of women. There were 2 LF in the RT arm vs. 15 in the OBS arm: at 5 years 0.4% RT vs. 3.2% OBS (p=0.0023, HR [95%CI] = 0.14 [0.03, 0.61]). With limited events, LF is not correlated with size, grade, margin status, or age. The rate of CBF at 5 years was 3.0% for the RT arm vs. 1.9% for the OBS arm (p=0.42, HR [95%CI] = 1.46 [0.59, 3.62]) and does not appear to be influenced by TAM use (3.6 versus 2.7% TAM). The DFS and OS results were excellent. Rate of grade 1-2 toxicity was 76% in the RT arm vs. 30% in the OBS arm, and the rate of ≥ 3 grade toxicities was 4% on both arms. Conclusions: In this “good risk” subset of DCIS, the LF rate was decreased significantly with the addition of RT. Longer follow-up is planned.
Correlation between the DCIS score and traditional clinicopathologic features in the prospectively designed E5194 clinical validation study.
Authors: Badve Sunil S. , Gray Robert James , Baehner Frederick L. , Solin Lawrence J. , Butler Steven M , Yoshizawa Carl , Shak Steven , Hughes Lorie L. , Page David L , Sledge George W. , Davidson Nancy E. , Perez Edith A. , Ingle James N. , Wood William C. , Sparano Joseph A.
Published: March 2020

1005

Background: We previously reported that in the E5194 clinical trial patients with ductal carcinoma in situ (DCIS) treated with wide local excision (WLE) without radiation (RT), the DCIS Score was significantly associated with 10 year risk of an ipsilateral breast event (IBE - recurrence of in situ or invasive carcinoma), whether evaluated as a continuous or categorical variable (P=0.02 for both). Here we evaluate correlation between DCIS Score and clinicopathologic (CP) features and if DCIS Score provides independent recurrence risk information. Methods: The study population included 327 women with DCIS prospectively selected for treatment with WLE without RT, including low-intermediate grade tumors ≤2.5 cm or high-grade ≤1 cm. CP variables included age, menopausal status, tamoxifen treatment (used in 29%) and expert centrally determined tumor size, grade, comedo necrosis, tumor type, and margin status. The association between DCIS Score and CP variables was examined by spearman rank correlation, and proportional hazards regression models were used to determine variables significantly associated with IBE. Results: Lesion size (p=0.009) and menopausal status (p=0.03) were significantly associated with IBE, while grade (p=0.69) and comedo necrosis (p=0.47) were not. DCIS Score was significantly associated with IBE after adjustment for CP features and tamoxifen use (p=0.02). DCIS Score was moderately correlated with grade (rs=0.46; 95% CI 0.37,0.54), percentage comedo necrosis (rs=0.49; CI 0.41,0.57), and lesion size (rs=0.18; CI 0.08,0.29) but not other features. Exploratory analyses in all CP subgroups, including the multicomponent Van Nuys Prognostic Index, showed a wide range of DCIS Scores in each subgroup. Concordance of the grades among readers was low: local vs parent central, 68%; local vs central nuclear grade, 45%; parent central vs central nuclear grade, 37%. Conclusions: DCIS Score is moderately correlated with grade, comedo necrosis, and tumor size. DCIS Score provides recurrence risk information independent of these features and identifies subjects with DCIS who are at high risk for local invasive and in-situ local recurrence after WLE alone.
Results of pulmonary metastasectomy for osteosarcoma in the pediatric age group.
Authors: Redwan Bassam , Schmidt Joachim , Bedetti Benedetta , Dirksen Uta , Juergens Herbert , Wiebe Karsten
Published: March 2020

10080

Background: Despite multimodal treatment concepts and complete surgical resection, prognosis in pediatric patients with pulmonary metastases from osteosarcoma has remained limited due to frequent relapse of disease. We investigated the results of an aggressive surgical approach. Methods: In a retrospective study, procedures and outcomes of pulmonary metastasectomy in the pediatric age group (up to 18 years) at our institution were analyzed over a period of 10 years (1999-2009). Resection of the primary osteogenic tumor and chemotherapy (CROSS-96-protocol and EURAMOS-1-protocol) were performed prior to thoracic surgery. Results: Forty-five pediatric patients (20 females) underwent pulmonary metastasectomies via sternotomy or sequential anterolateral thoracotomy at a mean age of 14 (6 -18) years. At primary surgery, a mean number of 7.9 (1 – 53) palpable suspicious lesions were resected per patient. Histo-pathological evaluation revealed 3.7 (0 – 40) metastases per patient. Mean total duration of surgery was 152 (46–323) minutes. Mean hospital stay was 10 days (3 – 33). In-hospital and 30-day mortality was 0%. The overall survival at 1 and 5 years was 97.8% and 77.3%, respectively. Mean disease-free-survival was 12.2 (3.2-38.0) months. In 19 (42.2 %) patients recurrent pulmonary metastases were detected and re-thoracotomies were required. Up to 7 procedures per patient were performed. Overall survival for patients undergoing more than one surgical procedure for recurrent lung metastases was not statistically different from survival in patients without relapse (p > 0.05). Survival was significantly better in patients initially presenting with less than 10 metastases (85.3 % vs. 54.1 % at 5 years, p = 0.028). Conclusions: Complete pulmonary metastasectomies are essential in pediatric osteosarcoma patients with lung metastasis. Repeated resections for recurrent relapses improve survival and may allow for long-term event-free-survival.
Targeting XRCC1 (X-ray repair cross-complementing gene 1) deficiency in tumors for personalized cancer therapy.
Authors: Madhusudan Srinivasan , Abdel-Fatah Tarek M. A. , Sultana Rebeka , Abbotts Rachel , Hawkes Claire , Seedhouse Claire , Green Andrew R. , Chan Stephen , Ellis Ian O.
Published: March 2020

1014

Background: XRCC1 is essential for DNA base excision repair, single strand break repair and nucleotide excision repair. XRCC1 deficiency promotes genomic instability and may increase cancer risk. Methods: We evaluated XRCC1 immunohistochemically in early stage breast (n=2046), ovarian (n=157), gastric (n=140), colorectal (n=250) and pancreaticobiliary cancers (n=240). Pre-clinically, we evaluated a panel of XRCC1 deficient and proficient Chinese hamster ovary and human cancer cell lines. Double strand break repair (DSB) inhibitors targeting ATM (KU55933), DNA-PKcs (NU7441) and ATR (NU6027) were evaluated for synthetic lethality and cisplatin alone or in combination with DSB inhibitors for chemopotentiation. Results: In breast cancer,XRCC1 loss (16%) was associated with higher grade (p<0.0001), loss of hormone receptors (p<0.0001), presence of triple negative (p<0.0001) and basal like phenotypes (p=0.001). Loss of XRCC1 was associated with a 2-fold increase in risk of death and metastasis (p<0.0001) and independently with poor outcome (p<0.0001). In ovarian cancer, XRCC1 was positive in 44% of tumour and was significantly associated with higher stage (p=0.001), clear/endometroid type (p=0.015) and sub-optimal debulking (p=0.004). XRCC1 positive tumours were more resistant to platinum chemotherapy (p=0.0001). XRCC1 positivity conferred a 2 fold increase of risk of death (p=0.002) and independently associated with poor survival (p=0.002). In gastric cancers, XRCC1 was positive in 37% of tumours. This was significantly associated with high stage disease (p=0.001) and poor survival (p=0.001). Pre-clinically, KU55933, NU7441 and NU6027 were synthetically lethal in XRCC1 deficient compared to proficient cells as evidenced by DSB accumulation, G2/M cell cycle arrest and apoptosis. XRCC1 deficient cells were hypersensitive to cisplatin which was enhanced by DSB repair inhibitors compared to in proficient cells. Conclusions: This is the largest study to confirm the clinical significance of XRCC1 expression in solid tumours. XRCC1 deficiency in human tumours may be suitable for synthetic lethality application and exploited for cisplatin chemotherapy potentiation.
Impact of adjuvant chemotherapy on recurrence-free survival in patients with pT1a/b hormone-negative and HER2-positive breast cancer.
Authors: Migdady Yazan , Sikov William M. , Sakr Bachir Joseph , Olszewski Adam J.
Published: March 2020

1034

Background: T1ab triple-negative (TN) or Her-2-positive (H2+) breast cancers are reported to pose relatively high risk of relapse, but benefits of adjuvant chemotherapy are uncertain. We studied the impact of chemotherapy on recurrence-free survival in this group. Methods: Records of all consecutive cases diagnosed in Brown-affiliated centers in 2000 - 2010 were reviewed. Factors influencing chemotherapy decision were studied with logistic regression, and recurrence-free interval (RFI) with a Cox proportional hazard model and Kaplan-Meier estimator. Results: Among 1415 screened T1a/b N0 cases, 161 were eligible (57 TN; 104 HER2+), with a median age of 57 years; 66% tumors were T1b. 20% of patients underwent mastectomy, 76% received radiation and 30% hormonal therapy. Adjuvant chemotherapy was recommended in 53% of cases. Younger age (p<10-6), stage T1b (p<10-5), high grade (p=0.001), HER2+/ERPR- status (p=0.017) and diagnosis after 2006 (p=0.007) were significantly predictive of the medical oncology recommendation. There was a significant trend with decrease in anthracycline (p<0.001) and increase in taxane use (p<0.001). With a median follow up of 46 months, the 5-year rate of relapse was 6.1% (95%CI 2.7-13.9%), somewhat higher in T1b tumors (8.1%) and without detectable difference in TN/HER2+ subgroups. In a univariate analysis chemotherapy did not significantly impact the recurrence-free interval (HR=0.45; 95%CI 0.09-2.34; p=0.32), however there was a detectable benefit (p=0.02) for T1b tumors in a multivariable Cox model including age (p=0.02) and LVI (p=0.01). The histology, type of surgery and year of diagnosis were not significant. There were no relapses among ER/PR+ patients who received hormonal therapy or HER2+ patients who received trastuzumab. Conclusions: The risk of relapse in biologically aggressive T1ab breast cancers is very low with judicious use of adjuvant therapy. The benefit of chemotherapy is likely restricted to the highest-risk patients with T1b tumors, lymphovascular invasion and younger age.
In vivo isolation of circulating tumor cells in non-small cell lung cancer (NSCLC) patients by a medical device.
Authors: Gasiorowski Lukasz , Herold Stefanie , Kim Phillip Sangwook , Schmitz Arndt , Krahn Thomas , Morgenthaler Nils G. , Dworacki Grzegorz , Luecke Klaus , Dyszkiewicz Wojciech
Published: March 2020

10536

Background: Currently, circulating tumor cells (CTCs) are isolated in vitro from small limited volumes of blood samples. Furthermore, CTC results for NSCLC as a prognostic and stratification biomarker are scarce. The aim of the study was to assess a functionalized and structured medical wire (FSMW) for in vivo isolation of CTCs directly from the blood of NSCLC patients, and to compare it to the Cell Search method. Methods: The device was inserted in a cubital vein through a standard cannula for thirty minutes. The interaction of target CTCs with the FSMW was mediated by an antibody directed against the epithelial cell adhesion molecule (EpCAM). To confirm the CTCs binding to the wire, the immunohistochemical staining against EpCAM as well as CD45 for negative cell selection was performed. There were 72 applications of the wire in 48 stage I-IIIB NSCLC patients (12 double applications) and 12 non cancer patients. Enumeration data was available for 34 NSCLC patients and 8 non cancer patients. For 34 patients, samples were also tested in the Cell Search system. Results: The device was well tolerated in all 72 applications without side effects. We obtained in vivo isolation of CTCs in 32 of 34 NSCLC patients (94.1%) with a median (range) of 13 (0-300) CTCs. The sensitivity was similar for early and late stage NSCLC patients. In the non-cancer patients, no CTCs were detected (100 % specificity). In 2 of 34 samples (5.8%), CTCs were detected by the Cell Search method. In all matched pairs, the FSMW detected the same number or more CTCs compared to the Cell Search method. Conclusions: Whilst well tolerated without side effects, the CTC detection rate of the FSMW in NSCLC patients was >90%. In contrast, <10% detection was obtained using the Cell Search analysis. No CTCs were detected in non-cancer patients. This proof of concept study may have important clinical implications, as the implementation of the device into clinical practice may improve early detection, prognosis and therapy monitoring of NSCLC patients. The method may also allow the molecular analysis of the CTCs, with the possibility of establishing more personalized treatment regiments.
Effect of the loss of the type III TGFβ receptor during tumor progression on tumor microenvironment: Preclinical development of TGFβ inhibition and TGFβ-related biomarkers to enhance immunotherapy efficacy.
Authors: Hanks Brent Allen , Holtzhausen Alisha , Gimpel Petra , Jamieson Rebekah , Campbell Olivia M. , Sun Lihong , Augustine Christina K. , Tyler Douglas S. , Osada Takuya , Morse Michael , Ling Leona E. , Lyerly H. Kim , Blobe Gerard C.
Published: March 2020

10563

Background: Overall, the clinical efficacy of tumor immunotherapy has been limited. Our incomplete understanding of the complex interplay between tumors and the immune microenvironment has contributed to these modest outcomes. Our work has revealed that several tumors downregulate the expression of the type III TGFβ receptor (TβRIII) with progression. TβRIII is shed from the cell surface to generate soluble TβRIII (sTβRIII) which is capable of sequestering TGFβ. Methods and Results: Using both breast cancer and melanoma tumor models we have demonstrated that the loss of TβRIII expression is associated with diminished tumor infiltrating CD8+ T cells and increased regulatory T cells (Tregs) within the tumor microenvironment. Our data implies that these alterations correlate with suppressed tumor antigen-specific T cell responses and more rapid disease progression. We show that these changes are due to enhanced TGFβ signaling within the immune compartment of the tumor microenvironment resulting in enhanced expression of the indoleamine 2,3-dioxygenase immunoregulatory enzyme by local plasmacytoid dendritic cells (DCs) as well as increased expression of the Treg-recruiting CCL22 chemokine by local myeloid DCs. Microarray analysis indicates that these same gene expression associations also exist in human breast cancers. Consistent with these studies, we have demonstrated that TGF-β inhibition synergistically enhances the efficacy of a Her2/neu vaccine in a breast cancer model and that plasma levels of sTβRIII correlate with clinical response and overall survival in stage III melanoma patients. Conclusions: We have elucidated a novel mechanism that tumors utilize to suppress the generation of anti-tumor immunity by establishing a link between the loss of an endogenous suppressor of tumor metastasis, TβRIII, and the generation of an immunotolerant tumor microenvironment. We are pursuing a phase I clinical trial to investigate the efficacy of combining a TGF-β inhibitor with a tumor vaccine while also determining if sTβRIII may function as a predictive biomarker for this approach.
Online biomarker validation of survival-associated biomarkers in breast and ovarian cancer using microarray data of 3,862 patients.
Authors: Gyorffy Balazs , Lanczky Andras , Szallasi Zoltan
Published: March 2020

10571

Background: The pre-clinical validation of prognostic gene candidates in large independent patient cohorts is a pre-requisite for the development of robust biomarkers. Today, curated microarray cohorts combined with appropriate clinical data offer a cost effective tool to prescreen potential new biomarkers. In present study we expanded our online Kaplan-Meier plotter tool to assess the effect of genes on ovarian cancer prognosis. Methods: Gene expression data and survival information of breast and ovarian cancer patients were downloaded from GEO and TCGA. To analyze the prognostic value of the selected gene in the various cohorts the patients are divided into two groups according to the quantile expression of the gene. Filtering is implemented for stage, grade, and histology subtypes. Follow-up threshold is implemented to exclude long-term effects. A Kaplan-Meier survival plot is generated and significance is computed in the R statistical environment using Bioconductor packages. The combination of several probe sets can be employed to assess the mean of their expression as a multigene predictor of survival. Results: All together 1,390 ovarian cancer patients and 2,472 breast cancer patients were entered into the database. These groups can be compared using relapse free survival (n=2,324 in breast cancer and 1,090 in ovarian cancer) or overall survival (n=464 and n=1,287). We used this integrative data analysis tool to validate the prognostic power of 37 ovarian cancer associated biomarkers identified in the literature. Of these, CA125 (p=3.7e-5, HR=1.4), CDKN1B (p=5.4e-5, HR=1.4), KLK6 (p=0.002, HR=0.79), IFNG (p=0.004, HR=0.81), P16 (p=0.02, HR=0.66) and BIRC5 (p=0.00017, HR=0.75) were associated with survival. Conclusions: We set up a global online biomarker validation platform to mine all available microarray data to assess the prognostic power of 22,277 genes in 2,472 breast and 1,390 ovarian cancer patients. Registration-free online access at: http://www.kmplot.com/.
A gene expression profile test that distinguishes ovarian from endometrial cancers.
Authors: Lal Anita , Panos Rebecca , Marjanovic Mira , Walker Michael , Fuentes Eloisa , Kapp Daniel Stuart , Henner William David , Buturovic Ljubomir J , Miller Meredith Halks
Published: March 2020

10576

Background: The differential diagnosis between primary epithelial ovarian and endometrial cancers is often unresolved because the histologic subtypes of these two tumor types can have very similar histology and immunohistochemical appearance. Here we report the development and validation of a gene expression profile (GEP) diagnostic test (Pathwork Tissue of Origin Endometrial Test) that distinguishes ovarian and endometrial cancers in formalin-fixed, paraffin-embedded (FFPE) specimens using a 316–gene classification model. Methods: The test was clinically validated in a blinded study using a pre-specified algorithm and microarray data files for 75 metastatic, poorly differentiated or undifferentiated primary FFPE tumor specimens that had either a known clinical diagnosis of ovarian or endometrial cancer and belonged to one of the 14 ovarian and endometrial WHO histologic subtypes on the test panel. Results: Classification biomarkers, empirically selected by machine learning, included several genes such as homeobox transcription factors and kallikrein peptidases with known function in the biology of ovarian and endometrial cancers. The Tissue of Origin Endometrial Test accurately identified the primary site for 94.7% (95% CI, 87% to 99%) of ovarian and endometrial cancers. Other measures of test performance include an area under the ROC curve of 0.997 and a diagnostic odds ratio of 406. Test performance did not change significantly when stratified by specimens from metastases (90.5%) or by poorly differentiated and undifferentiated primary tumors (96.3%). All stages of ovarian and endometrial cancers were included in the validation study and had agreements of 85% to 100% with the clinical diagnosis. In a precision study, concordance in test results was 100%. Reproducibility in test results between three laboratories had a concordance of 94.3%. Conclusions: The GEP test identified specific ovarian and endometrial cancer morphologies even when a clear distinction could not be made by histologic criteria. The GEP test can aid in resolving an important differential diagnostic question in gynecologic oncology and may impact clinical management of these patients as well as entry opportunities into clinical trials.
Specific and sensitive detection of BRAF and KRAS mutations in clinical samples.
Authors: Kelchner Vanessa , Chupreta Sergey , Mishra Anjali , Beaubien Ron , Kurihara Laurie , Laliberte Julie , Mikheykin Andrey , Beer David G. , Makarov Vladimir
Published: March 2020

10587

Background: The development of highly sensitive and specific genotyping assays that are suitable for clinical research and molecular diagnostics opens new opportunities for the detection, assessment, and research of cancer. Swift Biosciences has developed myT Primer qPCR technology which has unique structural and thermodynamic properties that enables highly sensitive mismatch discrimination. The myT Primer reagents can detect 1% mutant BRAF or KRAS present in a background of 103 wild-type genomic DNA copies with no background signal from wild-type. A separate ultrasensitive BRAF format has been developed which enables the detection of a single mutant BRAF copy in > 104 wild-type genomic DNA copies, representing 0.01% detection. Methods: To evaluate the performance on clinical samples, DNA was prepared from 26 melanoma, 40 colorectal, and 49 lung tumor fresh frozen and FFPE samples, and their corresponding normal adjacent samples. qPCR was performed using standard cycling conditions in single tube format with allele-specific myT primers to assess two BRAF alleles or seven KRAS alleles. Performance of the assay was evaluated on the ABI 7500, CFX96, and Roche LightCycler. A subset of samples were selected for validation by Sanger sequencing. Results: Mutations of BRAF in melanoma, colorectal, and lung tumors were observed to be 46%, 5%, and 2%, in concordance with published data for the frequency of BRAF mutations. Mutations of KRAS in colorectal cancer were observed to be in 17/40, or 42% of samples, consistent with published reports of KRAS in colorectal cancer. 34% of lung cancer samples had a KRAS mutation, also consistent with available statistics. Mutation status was confirmed with Sanger sequencing in the subset of selected samples. Conclusions: The extreme selectivity of the myT BRAF Primers makes them well suited for genotyping of conventional FFPE and frozen tissue samples, whereas the ultrasensitive format is ideal for use with difficult samples such as needle biopsies, CTCs, and serum. The extreme selectivity of these primers results in a definitive Yes/No answer and eliminates the need to use a delta Ct method.
Activation of angiogenic pathway in the prediction of pathologic response to bevacizumab-based neoadjuvant therapy in breast cancer.
Authors: Lopez-Vega Jose Manuel , Calvo Elena Galve , Plazaola Arrate , Morales Serafin , Hernando Blanca , Gomez Rosa Maria Sanchez , Alvarez Isabel , Anton Antonio , Illarramendi Jose J. , De Juan Ana , Martinez Purificación , Lahuerta Ainhara , Llombart Cussac Antonio , Garcia Gonzalez Maria , Lao Juan , Boni Valentina , Puertolas Teresa , Sherer Stefan , Sabariz Luis , Garcia-Foncillas Jesus
Published: March 2020

10595

Background: To evaluate potential biomarkers of pathological response to bevacizumab-based neoadjuvant therapy in untreated breast cancers (BC) patients recruited in a phase II, multicenter clinical trial. Methods: Patients received a single infusion of bevacizumab (15 mg/ kg) (C1) 3 weeks prior to the beginning of neoadjuvant chemotherapy (NAC) consisting in 4 cycles of docetaxel (60 mg/mq), doxorubicin (50 mg/mq) and bevacizumab (15 mg/ kg) every 21 days (C2-C5) following by surgery. Biomarker expression was assessed by immunohistochemistry (Ki67, CD31, CD31/Ki67, VEGFR2, pVEGFR2 [Y951]) before and after bevacizumab infusion (C1). Gene expression was analyzed using Affimetrix Human Gene ST 1.0. Results: This analysis was performed on 73 patients (49 yr, range 29-70). Twenty (27%) patients obtained best response (G4-G5) whether 50 (68%) were considered as no responder (G1-G2-G3). Response was associated with negative estrogen receptors expression (p=0.02) and high Ki67 basal and after C1 expression (p=0.009 and p=0.01). Six (54%) of the triple negative tumors were responders (p=0.05). Interestingly, change in pVEGFR2 [Y951] staining induced by bevacizumab administration was found significantly associated with response (p=0.0). Decrease in the phosphorilation status of VEGFR2 (Y951) >70% yielded a receiver operating characteristic (ROC) curve area of 0.681 (95% CI: 0.536 - 0.825) with 84% sensitivity and 95% specificity. The positive and negative predictive values for this marker were 60% and 64%, respectively. The change in phosphorilation status of VEGFR2p remains a significant predictor biomarker of response in multivariate analysis (OR=0.9, IC%95 0.96-0.99, p=0.04) after adjusting for clinical-pathological characteristics. Conclusions: These findings suggest the role of the phosphorilation status of VEGFR2 as predictive biomarkers of pathological response to bevacizumab in neoadjuvant setting in breast cancer.
Response and long-term outcomes after neoadjuvant chemotherapy: Pooled dataset of patients stratified by molecular subtyping by MammaPrint and BluePrint.
Authors: Gluck Stefan , De Snoo Femke , Peeters Justine , Somlo George , Van T Veer Laura
Published: March 2020

10597

Background: Classification of breast cancers into molecular subtypes may be important for the proper selection of therapy for patients with early breast cancer. Previous analyses had shown that breast cancer subtypes have distinct clinical outcome (Sorlie, PNAS, 2001; Esserman, BCRT, 2011). Herein, we analyze using MammaPrint together with an 80-gene molecular subtyping profile (BluePrint) the response to neo-adjuvant chemotherapy and long term outcomes. Methods: This study was carried out on data from 144 patients from the I-SPY I trial; 232 patients from biomarker discovery program at MD Anderson (133 and 99 respectively; Hess, 2006, JCO; Iwamoto, 2011, BCRT); and 68 patients from City of Hope (Somlo, ASCO, 2010). All patients were treated in the neo-adjuvant setting with standard chemotherapy. MammaPrint and BluePrint were determined on 44K Agilent arrays run at Agendia or available through the I-SPY 1 data portal, or from Affymetrix U133A arrays. MammaPrint and BluePrint resulted in 4 distinct molecular groups: Luminal A (MammaPrint Low-risk/Luminal-type), Luminal B (MammaPrint High-risk/Luminal-type), Basal-type and HER2-type. Results: The overall pCR of this patient cohort was 22% but differed substantially among the subgroups. pCR was observed in 5% of the Luminal-A samples and 10% of Luminal-B, in 39% of the HER2-type samples and in 33% of the Basal-type samples. Patients with Basal-type tumors had a 5-year DFS of 71%; HER2-type had a 5-year DFS of 67%(n=71); 69% in HER2-type subgroup not treated with HER2-targeted therapy (n=45); Luminal-B type had a 5-year DFS of 77% and Luminal-A type showed 5-year DFS of 95%. Conclusions: We observed marked differences in response and DFS to neo-adjuvant treatment in groups stratified by MammaPrint and BluePrint. These findings confirm differences in chemotherapy response among molecular subgroups and indicate that the BluePrint and MP profile used for this analysis helps to further establish a clinical correlation between molecular subtyping and treatment outcomes.
Correlation between in vitro chemotherapy sensitivity and PARP-1 expression in patients with breast cancer.
Authors: Liedtke Cornelia , Packeisen Jens , Denkert Carsten , Kiesel Ludwig , Vogt Ulf , Mueller Berit , Hess Kenneth R. , Buerger Horst
Published: March 2020

10627

Background: Based on its potential use as a therapeutic target through PARP inhibitors expression of Poly-A-Ribose-Polymerase-1 (PARP-1) has come into scientific focus. Furthermore, it could be demonstrated that cytoplasmic PARP-1 expression varies depending on molecular breast cancer subtypes and that it correlates with an increased response to neoadjuvant taxane-anthrazykline containing chemotherapy (von Minckwitz et al., J Clin Oncol 2011). In-vitro-chemotherapy sensitivity and resistance assays (CSRAs) are a means to directly measure chemotherapy sensitivity in a given tumor uninfluenced by host factors. Methods: We conducted a systematic immunohistochemical tissue-microarray (TMA)-based analysis of 550 samples of invasive breast cancers to evaluate the expression of a set of molecular markers including estrogen receptor (ER), progesterone receptor (PR) and HER2 as well as PARP-1. Triple negative breast cancers (TNBC) were identified through lack of (over-)expression of ER, PR and HER2. All carcinomas were analyzed in an in vitro CSRA protocol for epirubicin/docetaxel (ED) and epirubicin/cyclophosphamide (EC). In-vitro-chemotherapy sensitivity was analyzed using an adenosine triphosphate (ATP) bioluminescence assay. Results: Moderate/high expression of PARP-1 was found in 48 and 33% of cases with TNBC and non-TNBC, respectively (p=0.015). No correlation between TNBC phenotype and cytoplasmic expression was observed. However, increased expression of both cytoplasmic and nuclear PARP-1 was correlated with an increased in-vitro sensitivity against ED (p=0.012 and 0.025, respectively) but not EC (p=0.27 and 0.62, respectively). Conclusions: Our results support previous observations demonstrating a significant correlation between expression of PARP-1 and an increased sensitivity against taxane-anthracycline chemotherapy independent of tumor phenotype.
Chemotherapy of methioninase-synchronized S/G2 phase-blocked cancer cells identified by cell cycle-specific fluorescent reporters.
Authors: Yano Shuya , Li Shukuan , Han Qinghong , Tan Yuying , Fujiwara Toshiyoshi , Hoffman Robert M.
Published: March 2020

1063

Background: Cancer cells of all types have a generally elevated requirement for methionine compared to normal cells. This phenomenon is termed methionine-dependence and may be due to excessive methylation reactions in cancer cells, since methionine is the global source of cellular methyl groups (Biochim. Biophys. Acta, Reviews on Cancer 738, 49-87, 1984). Deprivation of methionine selectively arrests cancer cells during late S-phase (Proc. Natl. Acad. Sci. USA 77, 7306-7310, 1980), where they are highly sensitive to chemotherapy drugs which damage DNA (J. Natl. Cancer Inst. 76, 629-639, 1986). Methods: Cancer cells, transformed to express different color fluorescent reporters during specific phases of the cell cycle (Cell 132, 487-498, 2008), were used to monitor the onset of the S/G2-phase block due to methionine deprivation effected by recombinant methioninase (rMETase). The S/G2-phase blocked cancer cells fluoresced yellow or green in contrast to cancer cells in G1 which fluoresced red. Cancer cells, including MKN45 stromal cancer and MCF-7 breast cancer, synchronously blocked in S/G2-phase by rMETase, were identified by their yellow-green fluorescence and allowed to accumulate to the maximum extent. At the point of maximum yellow/green cells in the culture, the cells were administered chemotherapy drugs which interact with DNA or block DNA synthesis such as doxorubicin, cisplatin or 5-fluorouracil. We termed this procedure color-coded chemotherapy (CCC). Results: CCC was highly effective against the cancer cells (90% cell kill). In contrast, treatment of cancer cells with drugs only, and without rMETase-effected S/G2-phase synchrony, led to the majority of the cancer cell population being blocked in G1 phase (red fluorescent) where they were resistant to the drugs (40% cell kill). Conclusions: CCC, which identifies, by fluorescent color, when cancer cells are blocked in S/G2-phase by a unique cell-cycle-blocking agent, rMETase, demonstrates the potential of cell-synchronization-based chemotherapy.