bluuebunny/crossref_metadata_2025 huggingface dataset:
Understanding how Eastern European migrants use and experience UK health services: a systematic scoping review
Authors: Phung Viet-Hai , Asghar Zahid , Matiti Milika , Siriwardena A. Niroshan
Published: March 2020

Background

The UK has experienced significant immigration from Eastern Europe following European Union (EU) expansion in 2004, which raises the importance of equity and equality for the recent immigrants. Previous research on ethnic health inequalities focused on established minority ethnic groups, whereas Eastern European migrants are a growing, but relatively under-researched group. We aimed to conduct a systematic scoping review of published literature on Eastern European migrants’ use and experiences of UK health services.

Methods

An initial search of nine databases produced 5997 relevant publications. Removing duplicates reduced the figure to 2198. Title and abstract screening left 73 publications. Full-text screening narrowed this down further to 10 articles, with three more from these publications to leave 13 included publications. We assessed publications for quality, extracted data and undertook a narrative synthesis.

Results

The included publications most commonly studied sexual health and family planning services. For Eastern European migrants in the UK, the most commonly cited barriers to accessing and using healthcare were limited understanding of how the system worked and language difficulties. It was also common for migrants to return to their home country to a healthcare system they were familiar with, free from language barriers. Familial and social networks were valuable for patients with a limited command of English in the absence of suitable and available interpreting and translating services.

Conclusions

To address limited understanding of the healthcare system and the English language, the NHS could produce information in all the Eastern European languages about how it operates. Adding nationality to the Electronic Patient Report Form (EPRF) may reveal the demand for interpretation and translation services. Eastern European migrants need to be encouraged to register with GPs to reduce A&E attendance for primary care conditions. Many of the issues raised will be relevant to other European countries since the long-term outcomes from Brexit are likely to influence the level of Eastern European and non-Eastern European migration across the continent, not just the UK.
The imperative of evidence-based health workforce planning and implementation: lessons from nurses and midwives unemployment crisis in Ghana
Authors: Asamani James Avoka , Amertil Ninon P. , Ismaila Hamza , Akugri Francis Abande , Nabyonga-Orem Juliet
Published: March 2020

Following periods of health workforce crisis characterised by a severe shortage of nurses, midwives and doctors due to low production rates and excessive out-migration, the Government of Ghana through the Ministry of Health (MOH) responded by expanding training and allowing private sector involvement in the training of health workers especially nurses and midwives. This resulted in substantial increases in the production levels of nurses and midwives even above the projections of the MOH. In this paper, we discuss how a strategy that was seemingly well planned suffered a decade of uncorrected implementation lapses resulting in a lingering need-based shortage of nurses and midwives at service delivery points whilst thousands of trained nurses and midwives remained unemployed for up to 4 years and constantly protesting for jobs. In the short term, we argue that the Government of Ghana would need to increase investment to recruit trained and unemployed nurses and midwives whilst a comprehensive health labour market analysis is conducted to provide robust evidence towards the development of a long-term health workforce plan that would guide future production of nurses and midwives. The Government of Ghana may also explore the option of a managed migration programme to export nurses/midwives to countries that are already destinations to individual migration initiatives in a bid to mitigate the potential skill loss associated with long periods of unemployment after training, especially for those who trained from the private institutions.
Evaluating research investment and impact at a regional Australian Hospital and Health Service: a programme theory and conceptual framework
Authors: Edelman Alexandra , Brown Amy , Pain Tilley , Larkins Sarah , Harvey Gillian
Published: March 2020

Background

Health systems in Australia and worldwide are increasingly expected to conduct research and quality improvement activities in addition to delivering clinical care and training health professionals. This study aims to inform a research impact evaluation at a regional Australian Hospital and Health Service by developing a programme theory showing how research investment is expected to have impact.

Methods

This qualitative study, representing the first phase of a larger mixed methods research impact evaluation at the Townsville Hospital and Health Service (THHS), adopts a realist-informed design involving the development of a programme theory. Data were obtained between February and May 2019 from strategic documentation and interviews with six current and former health service executives and senior employees. Inductive themes were integrated into a conceptual framework to visually represent the programme theory.

Results

Research at THHS has developed organically as the service has matured into a regional tertiary referral service serving a diverse rural and remote population across northern Queensland. Throughout this journey, individual THHS leaders often adopted a research development mantle despite disincentives arising from a performance-driven reporting and activity-based funding service context. Impact expectations from research investment at THHS were identified in the categories of enhanced research activity and capacity among clinicians, and improved clinical practice, health workforce capability and stability, and patient and population health. Seven contextual factors were identified as potential enablers or obstacles to these impact expectations and ambitions.

Conclusions

By identifying both relevant impact types and key contextual factors, this study offers programme theory to inform a planned research impact evaluation at THHS. The conceptual framework may be useful in other regionally based health service settings. More broadly, there are opportunities for future research to test and refine hybrid versions of linear and realist research impact evaluation models that combine resource-intensive, theory-driven approaches with policy practicality.
Alternatively activated macrophages; a double-edged sword in allergic asthma
Authors: Abdelaziz Mohamed Hamed , Abdelwahab Sayed F. , Wan Jie , Cai Wei , Huixuan Wang , Jianjun Cheng , Kumar Kesavan Dinesh , Vasudevan Aparna , Sadek Ahmed , Su Zhaoliang , Wang Shengjun , Xu Huaxi
Published: March 2020

Background

Macrophages are heterogenous phagocytic cells with an important role in the innate immunity. They are, also, significant contributors in the adaptive immune system. Macrophages are the most abundant immune cells in the lung during allergic asthma, which is the most common chronic respiratory disease of both adults and children. Macrophages activated by Th1 cells are known as M1 macrophages while those activated by IL-4 and IL-13 are called alternatively activated macrophages (AAM) or M2 cells. AAM are subdivided into four distinct subtypes (M2a, M2b, M2c and M2d), depending on the nature of inducing agent and the expressed markers.

Body

IL-4 is the major effector cytokine in both alternative activation of macrophages and pathogenesis of asthma. Thus, the role of M2a macrophages in asthma is a major concern. However, this is controversial. Therefore, further studies are required to improve our knowledge about the role of IL-4-induced macrophages in allergic asthma, through precisive elucidation of the roles of specific M2a proteins in the pathogenesis of asthma. In the current review, we try to illustrate the different functions of M2a macrophages (protective and pathogenic roles) in the pathogenesis of asthma, including explanation of how different M2a proteins and markers act during the pathogenesis of allergic asthma. These include surface markers, enzymes, secreted proteins, chemokines, cytokines, signal transduction proteins and transcription factors.

Conclusions

AAM is considered a double-edged sword in allergic asthma. Finally, we recommend further studies that focus on increased selective expression or suppression of protective and pathogenic M2a markers.
Characterization of HIV-1 uncoating in human microglial cell lines
Authors: Ingram Zachary , Taylor Melanie , Okland Glister , Martin Richard , Hulme Amy E.
Published: March 2020

Background

After viral fusion with the cell membrane, the conical capsid of HIV-1 disassembles by a process called uncoating. Previously we have utilized the CsA washout assay, in which TRIM-CypA mediated restriction of viral replication is used to detect the state of the viral capsid, to study the kinetics of HIV-1 uncoating in owl monkey kidney (OMK) and HeLa cells. Here we have extended this analysis to the human microglial cell lines CHME3 and C20 to characterize uncoating in a cell type that is a natural target of HIV infection.

Methods

The CsA washout was used to characterize uncoating of wildtype and capsid mutant viruses in CHME3 and C20 cells. Viral fusion assays and nevirapine addition assays were performed to relate the kinetics of viral fusion and reverse transcription to uncoating.

Results

We found that uncoating initiated within the first hour after viral fusion and was facilitated by reverse transcription in CHME3 and C20 cells. The capsid mutation A92E did not significantly alter uncoating kinetics. Viruses with capsid mutations N74D and E45A decreased the rate of uncoating in CHME3 cells, but did not alter reverse transcription. Interestingly, the second site suppressor capsid mutation R132T was able to rescue the uncoating kinetics of the E45A mutation, despite having a hyperstable capsid.

Conclusions

These results are most similar to previously observed characteristics of uncoating in HeLa cells and support the model in which uncoating is initiated by early steps of reverse transcription in the cytoplasm. A comparison of the uncoating kinetics of CA mutant viruses in OMK and CHME3 cells reveals the importance of cellular factors in the process of uncoating. The E45A/R132T mutant virus specifically suggests that disrupted interactions with cellular factors, rather than capsid stability, is responsible for the delayed uncoating kinetics seen in E45A mutant virus. Future studies aimed at identifying these factors will be important for understanding the process of uncoating and the development of interventions to disrupt this process.
CPAP (Continuous Positive Airway Pressure) is an effective and stable solution for heart sparing radiotherapy of left sided breast cancer
Authors: Allen Aaron M. , Ceder Yasmin Korzets , Shochat Tzippy , Fenig Eyal , Popovtzer Aron , Bragilofsky Dimitry , Alfassy Adi , Allon Helena
Published: March 2020

Purpose

Limiting the heart dose in left sided breast cancer radiotherapy is critical. We sought to study the effect of using CPAP (continuous positive airway pressure) as an aid in reducing heart dose in breast cancer radiotherapy.

Methods

Patients with left sided breast cancer receiving adjuvant radiotherapy were enrolled on a prospective IRB (institutional review board) approved clinical trial utilizing CPAP during radiotherapy. Each patient was simulated and planned with and without CPAP and the best dosimetric results determined the patient’s treatment. Data on the differences in lung and heart volume and position as well as boost cavity position with and without CPAP were analyzed.

Results

Twenty-four women from 10/16 to 10/18 were enrolled. Seven patients were not treated on study; only two of these were due to treatment issues. Median age was 54 years. 70% had breast only radiation and 30% were treated to breast\CW (chest wall) and regional nodes. The median lung volume with CPAP was 60% larger than without CPAP. (1637 vs. 996 cc) p < 0.001. The median heart volume decreased 12% with CPAP. (338 vs. 382 cc) In regards to the DVH, CPAP decreased mean heart dose from 3.02 to 1.6Gy (p = .0075) and V20 of the lungs from 17.1 to 13.8 with CPAP but this was not significant.

Conclusion

CPAP assisted radiotherapy was tolerable and produced superior treatment plans in left sided breast cancer. This method is worthy of further investigation as a method to normal tissue sparing treatment of left sided breast cancer patients.
Persistent dyslipidemia in treatment of lysosomal acid lipase deficiency
Authors: Pritchard Amanda Barone , Strong Alanna , Ficicioglu Can
Published: March 2020

Background

Lysosomal acid lipase deficiency (LALD) is an autosomal recessive inborn error of lipid metabolism characterized by impaired lysosomal hydrolysis and consequent accumulation of cholesteryl esters and triglycerides. The phenotypic spectrum is diverse, ranging from severe, neonatal onset failure to thrive, hepatomegaly, hepatic fibrosis, malabsorption and adrenal insufficiency to childhood-onset hyperlipidemia, hepatomegaly, and hepatic fibrosis. Sebelipase alfa enzyme replacement has been approved by the Food and Drug Administration for use in LALD after demonstrating dramatic improvement in transaminitis and dyslipidemia with initiation of enzyme replacement therapy.

Methods

A chart review was performed on 2 patients with childhood-onset, symptomatic LALD with persistent dyslipidemia despite appropriate enzyme replacement therapy to identify biological pathways and risk factors for incomplete response to therapy.

Results

Two patients with attenuated, symptomatic LALD had resolution of transaminitis on enzyme replacement therapy without concomitant effect on dyslipidemia despite dose escalation and no evidence of antibody response to enzyme.

Conclusion

Enzyme replacement therapy does not universally resolve all complications of LALD. Persistent dyslipidemia remains a clinically significant issue, likely related to the complex metabolic pathways implicated in LALD pathogenesis. We discuss the possible mechanistic basis for this unexpected finding and the implications for curative LALD therapy.
Lived experience and attitudes of people with plantar heel pain: a qualitative exploration
Authors: Cotchett Matthew , Rathleff Michael Skovdal , Dilnot Matthew , Landorf Karl B. , Morrissey Dylan , Barton Christian
Published: March 2020

Background

Plantar heel pain is a common source of pain and disability. Evidence‐based treatment decisions for people with plantar heel pain should be guided by the best available evidence, expert clinical reasoning, and consider the needs of the patient. Education is a key component of care for any patient and needs to be tailored to the patient and their condition. However, no previous work has identified, far less evaluated, the approaches and content required for optimal education for people with plantar heel pain. The aim of this study was to gather the patients' perspective regarding their lived experience, attitudes and educational needs in order to inform the content and provision of meaningful education delivery approaches.

Methods

Using a qualitative descriptive design, semi‐structured interviews were conducted with participants with a clinical diagnosis of plantar heel pain. A topic guide was utilised that focused on the experience of living with plantar heel pain and attitudes regarding treatment and educational needs. Interviews were audio recorded, transcribed verbatim and analysed using the Framework approach. Each transcription, and the initial findings, were reported back to participants to invite respondent validation.

Results

Eighteen people with plantar heel pain were interviewed. Descriptive analysis revealed eight themes including perceptions of plantar heel pain, impact on self, dealing with plantar heel pain, source of information, patient needs, patient unmet needs, advice to others and interest in online education. Participants revealed doubt about the cause, treatment and prognosis of plantar heel pain. They also expressed a desire to have their pain eliminated and education individually tailored to their condition and needs. Respondent validation revealed that the transcripts were accurate, and participants were able to recognise their own experiences in the synthesised themes.

Conclusion

Plantar heel pain has a negative impact on health‐related quality of life. Participants wanted their pain eliminated and reported that their expectations and needs were frequently unmet. Health professionals have an important role to be responsive to the needs of the patient to improve their knowledge and influence pain and behaviour. Our study informs the content needed to help educate people with plantar heel pain.
Protocol for a randomised trial of early kangaroo mother care compared to standard care on survival of pre-stabilised preterm neonates in The Gambia (eKMC)
Authors: Brotherton Helen , Gai Abdou , Tann Cally J. , Samateh Ahmadou Lamin , Seale Anna C. , Zaman Syed M. A. , Cousens Simon , Roca Anna , Lawn Joy E.
Published: March 2020

Background

Complications of preterm birth cause more than 1 million deaths each year, mostly within the first day after birth (47%) and before full post-natal stabilisation. Kangaroo mother care (KMC), provided as continuous skin-to-skin contact for 18 h per day to fully stabilised neonates ≤ 2000 g, reduces mortality by 36–51% at discharge or term-corrected age compared with incubator care. The mortality effect of starting continuous KMC before stabilisation is a priority evidence gap, which we aim to investigate in the eKMC trial, with a secondary aim of understanding mechanisms, particularly for infection prevention.

Methods

We will conduct a single-site, non-blinded, individually randomised, controlled trial comparing two parallel groups to either early (within 24 h of admission) continuous KMC or standard care on incubator or radiant heater with KMC when clinically stable at > 24 h of admission. Eligible neonates (n = 392) are hospitalised singletons or twins < 2000 g and 1–24 h old at screening who are mild to moderately unstable as per a trial definition using cardio-respiratory parameters. Randomisation is stratified by weight category (< 1200 g; ≥ 1200 g) and in random permuted blocks of varying sizes with allocation of twins to the same arm. Participants are followed up to 28 ± 5 days of age with regular inpatient assessments plus criteria-led review in the event of clinical deterioration. The primary outcome is all-cause neonatal mortality by age 28 days. Secondary outcomes include the time to death, cardio-respiratory stability, hypothermia, exclusive breastfeeding at discharge, weight gain at age 28 days, clinically suspected infection (age 3 to 28 days), intestinal carriage of extended-spectrum beta-lactamase producing (ESBL) Klebsiella pneumoniae (age 28 days), and duration of the hospital stay. Intention-to-treat analysis will be applied for all outcomes, adjusting for twin gestation.

Discussion

This is one of the first clinical trials to examine the KMC mortality effect in a pre-stabilised preterm population. Our findings will contribute to the global evidence base in addition to providing insights into the infection prevention mechanisms and safety of using this established intervention for the most vulnerable neonatal population.

Trial registration

ClinicalTrials.gov NCT03555981. Submitted 8 May 2018 and registered 14 June 2018. Prospectively registered.
Protein A/G-based enzyme-linked immunosorbent assay for detection of anti-Pythium insidiosum antibodies in human and animal subjects
Authors: Jaturapaktrarak Chalisa , Payattikul Penpan , Lohnoo Tassanee , Kumsang Yothin , Laikul Aree , Pathomsakulwong Watcharapol , Yurayart Chompoonek , Tonpitak Walaiporn , Krajaejun Theerapong
Published: March 2020

Objectives

Pythiosis is a deadly infectious disease caused by Pythium insidiosum. Reports of both human and animal pythiosis are on the rise worldwide. Prognosis of the pythiosis patients relies on early diagnosis and prompt treatment. There are needs for an immunodiagnostic test that can detect the disease in both humans and animals. This study aims at reporting an optimized protocol for the development of a protein A/G-based enzyme-linked immunosorbent assay (ELISA) for the detection of anti-P. insidiosum antibody in multiple host species.

Results

A total of 25 pythiosis and 50 control sera, obtained from humans, horses, dogs, cats, and cows, were recruited for the assay development. With a proper ELISA cutoff point, all pythiosis sera can ultimately be distinguished from the control sera. The successfully-developed protein A/G-based ELISA can detect the anti-P. insidiosum antibodies in serum samples of both humans and animals. It is a versatile, feasible-to-develop, and functional immunodiagnostic assay for pythiosis.
Null controllability of a semilinear degenerate parabolic equation with a gradient term
Authors: Xu Fengdan , Zhou Qian , Nie Yuanyuan
Published: March 2020

This paper concerns the null controllability of a semilinear control system governed by degenerate parabolic equation with a gradient term, where the nonlinearity of the problem is involved with the first derivative. We first establish the well-posedness and prove the approximate null controllability of the linearized system, then we can get the approximate null controllability of the semilinear control system by a fixed point argument. Finally, the semilinear control system with a gradient term is shown to be null controllable.
Certain properties of difference operator and stability of Fréchet functional equation
Authors: Sukhonwimolmal Teerapol
Published: March 2020

Let M be a commutative monoid, and let B be a Banach space. We give a new recursive method to obtain a Gǎvruţa-type stability result for the functional equation Δyn+1f(x):=∑k=0n+1(−1)n+1+k(n+1k)f(x+ky)=0 via algebraic manipulations of the forward difference operator.
A cohort study of quality of life in partners of young breast cancer survivors compared to partners of healthy controls
Authors: Cohee Andrea , Storey Susan , Winger Joseph G. , Cella David , Stump Timothy , Monahan Patrick O. , Champion Victoria L.
Published: March 2020

Background

Partners of young breast cancer survivors (BCS) are at increased risk for deficits in quality of life (QoL). To intervene effectively, it is important to understand how the breast cancer experience impacts partners. The purpose of this study was to compare QoL between partners of young BCS and partners of healthy acquaintance controls.

Methods

Partners of young BCS (3–8 years post treatment and ≤ 45 years old at diagnosis) and partners of age-matched healthy acquaintance controls completed questionnaires on overall, physical (physical function, sexual difficulty), social (personal resources, sexual enjoyment, marital satisfaction, partner social support, social constraints, parenting satisfaction), psychological (depressive symptoms), and spiritual (behaviors, beliefs, and activities) QoL. Analyses included descriptive statistics and one-way ANOVA to compare partner groups on all study variables.

Results

Although partners of young BCS (n = 227) reported fewer social constraints (p < .001), they reported lower overall QoL (p < .001), fewer personal resources (p < .001), more sexual difficulty (p = .019), less sexual enjoyment (p = .002), less marital satisfaction (p = .019), more depressive symptoms (p = .024), and fewer spiritual behaviors (p < .001), beliefs (p = .001) and activities (p = .003) compared to partners of healthy acquaintance controls (n = 170). Additional analysis showed that perceptions that the relationship changed for the better since cancer, social constraints, partner social support, and depression predicted marital satisfaction among partners of young BCS.

Conclusions

Partners of young BCS are at risk for poorer overall, physical, social, psychological, and spiritual QoL compared to partners of healthy women. Interventions targeting QoL domains may enable partners to effectively support their partner and improve their QoL.
Adherence to Surveillance for Second Malignant Neoplasms and Cardiac Dysfunction in Childhood Cancer Survivors: A Childhood Cancer Survivor Study
Authors: Yan Adam P. , Chen Yan , Henderson Tara O. , Oeffinger Kevin C. , Hudson Melissa M. , Gibson Todd M. , Neglia Joseph P. , Leisenring Wendy M. , Ness Kirsten K. , Ford Jennifer S. , Robison Leslie L. , Armstrong Gregory T. , Yasui Yutaka , Nathan Paul C.
Published: March 2020

PURPOSE

To evaluate childhood cancer survivors’ adherence to surveillance protocols for late effects of treatment and to determine the factors affecting adherence.

METHODS

Between 2014 and 2016, 11,337 survivors and 2,146 siblings in the Childhood Cancer Survivor Study completed a survey ascertaining adherence to Children’s Oncology Group (COG) guidelines for survivors at high risk for second malignant neoplasms or cardiac dysfunction and to the American Cancer Society (ACS) cancer screening guidelines for average-risk populations. Adherence rates and factors affecting adherence were analyzed.

RESULTS

Median age at diagnosis was 7 years (range, 0-20.9 years), and median time from diagnosis was 29 years (range, 15-47 years). Among high-risk survivors, adherence to COG breast, colorectal, skin, and cardiac surveillance was 12.6% (95% CI, 10.0% to 15.3%), 37.0% (34.1% to 39.9%), 22.3% (21.2% to 23.4%), and 41.4% (40.1% to 42.7%), respectively. Among average-risk survivors, adherence to ACS breast, cervical, and colorectal screening was 57.1% (53.2% to 61.0%), 83.6% (82.7% to 84.5%), and 68.5% (64.7% to 72.2%), respectively. Twenty-seven percent of survivors and 20.0% of primary care providers (PCPs) had a survivorship care plan (SCP). For high-risk survivors, SCP possession was associated with increased adherence to COG breast (22.3% v. 8.1%; prevalence ratio [PR], 2.52; CI, 1.59 to 4.01), skin (34.8% v 23.0%; PR, 1.16; CI, 1.01 to 1.33), and cardiac (67.0% v 33.1%; PR, 1.73; CI, 1.55 to 1.92) surveillance. For high-risk survivors, PCP possession of a SCP was associated only with increased adherence to COG skin cancer surveillance (36.9% v 23.2%; PR, 1.24; CI, 1.08 to 1.43).

CONCLUSION

Guideline adherence is suboptimal. Although survivor SCP possession is associated with better adherence, few survivors and PCPs have one. New strategies to improve adherence are needed.
High expression of the chemokine receptor CXCR4 is associated with estrogen receptor-negative breast cancer
Authors: Wheler J. J. , Doane A. S. , Linkov I. , Hudis C. A. , Gerald W.
Published: March 2020

642

Background: Chemokine receptor CXCR4 and its ligand CXCL12 (SDF-1alpha) are important in the metastatic spread of breast cancer. Previous studies have shown that CXCR4 is overexpressed in breast cancers as compared to normal breast tissue and that estradiol increases levels of CXCL12. The association between CXCR4 and estrogen receptor (ER) status is unclear. Methods: We performed genome-wide molecular analysis of 61 primary breast cancer tissue samples. Total RNA was extracted and hybridized to Affymetrix HG-U133 oligonucleotide microarrays, and differentially expressed genes between groups were identified using a Welch t-test. CXCR4 protein expression was evaluated by immunohistochemistry (IHC) using a monoclonal antibody (R&D Systems, Minneapolis, MN). We characterized CXCR4 nuclear staining as high vs low-medium. Several clinico-pathologic variables were correlated with CXCR4 expression. Results: A predominantly nuclear staining pattern was noted for CXCR4. Of 61 primary tumors, 15 had high nuclear expression and 46 had low-medium expression. High levels of nuclear CXCR4 expression were significantly correlated with ER-negativity (p =0.0005). CXCR4 protein expression had no association with Her-2 status (gene copy number or IHC 3+), tumor size, or lymph node status. Using p<0.001, protein expression of CXCR4 was associated with 105 significantly differentially expressed genes including relative under expression of ER and ER-related genes and over expression of VEGF. Conclusion: High nuclear protein expression levels of CXCR4 in primary breast cancers are significantly associated with ER-negativity and with low differential expression of ER and ER-related genes. Since estrogen may play a role in CXCR4 activation, further investigation of the association of high CXCR4 expression and ER-negativity is planned.

No significant financial relationships to disclose.
Weekly paclitaxel in metastatic angiosarcoma. A FNCLCC French Sarcoma Group (GSF-GETO) phase II trial
Authors: Penel N. , Bui Nguyen B. , Bay J. O. , Cupissol D. , Ray-Coquard I. , Piperno-Neumann S. , Kerbrat P. , Fournier C. , Mahier C. , Blay J. Y.
Published: March 2020

10002

Background: Angiosarcomas (AS) are unfrequent tumors with aggressive metastatic spreading. Although no prospective clinical trial has been so far specifically dedicated to these advanced tumors, their treatments are usually anthracyclin-based. However, a single institution-based retrospective study has suggested that paclitaxel (P) may have some efficacy in metastatic AS [Fata F et al. Cancer 1999, 86, 2034–7]. The aim of the following phase II study is to prospectively evaluate the efficacy and tolerance of weekly P in metastatic AS. Methods: Eligible patients were as follows: =18 years-old, measurable histologically-proven metastatic AS, and either naïve or pretreated patients (pts). Pts were planned to receive P 80 mg/m2 on day 1, 8 and 15, every 28 days until progression or severe toxicity. The primary endpoint was the objective response rate after 2 cycles, according to RECIST. A two stages Simon‘s optimal design was used with p0=10%, p1=30%, a=0.05 and 80% power. Results: From 04/2005 to 10/2006, 30 pts were included in 12 centers. There were 19 female and 11 male, and the mean age was 63 (range 23–85). Main primaries were breast, skin or scalp, liver and kidney in 8, 8, 3 and 2 cases, respectively. 33% (10/30) of these AS occurred in irradiated fields (9 for breast adenocarcinoma). Seventy three per cent of the pts (22/30) had previous surgery and 47% (14/30) previous chemotherapy, including anthracyclin in all cases. The number of pts who received 3, 4, 5 and 6 cycles of P were 15, 11, 6 and 4, respectively. Grade (G) 4 toxicity was reported in 1 case (neutropenia). G2 and 3 toxicities were notified for 27/30 pts including myalgias in 15 cases (55%), leuco-neutropenia in 14 cases (51%), infections in 6 cases (22%), and anemia in 4 cases (15%). As of 12/2006, 23 pts were evaluable for response, with 4 (14%) PR, 14 (56%) SD and 7 (30%) PD. The overall tumor- control rate (PR+SD) was 16/23 (70% (95% CI:50–88%). Conclusions: Weekly paclitaxel induces a significant tumor control with manageable toxicity for metastatic AS.

No significant financial relationships to disclose.
Change in quantitative FDG-PET was significantly more accurate than change in size at predicting histopathologic response to neoadjuvant therapy in high grade soft tissue sarcomas
Authors: Evilevitch V. , Weber W. A. , Tap W. D. , Chow K. , Allen-Auerbach M. , Nelson S. D. , Eilber F. R. , Eckardt J. J. , Czernin J. , Eilber F. C.
Published: March 2020

10017

Background: Change in size by RECIST (Response Evaluation Criteria in Solid Tumors) has been the standard to assess response to therapy in non-GIST soft tissue sarcomas (STS). Although recent studies have demonstrated that Positron Emission Tomography with F18-fluorodeoxyglucose (FDG-PET) may be used to assess response, there has not been a direct comparison between these modalities. The aim of this study was to prospectively evaluate whether a change in quantitative FDG-PET or a change in size [computed tomography(CT)] was more accurate at predicting histopathologic response to neoadjuvant therapy in patients with high grade STS using a combined FDG-PET/CT scan. Methods: From 1/05 - 12/06 58 patients with resectable biopsy proven high grade STS scheduled to undergo neoadjuvant chemotherapy were prospectively enrolled in this study. Patients underwent FDG-PET/CT prior to and after neoadjuvant treatment (prior to surgery). Tumor FDG-uptake was quantified by standardized uptake values (SUV). Changes in tumor size were quantified according to RECIST. Following tumor resection, response was assessed histopathologically. Patients with = 10% viable tumor cells were classified as responders. To date, 36 patients have completed the study and are the subject of this analysis. Results: In histopathologic responders (n=10, 28%), reduction of tumor FDG-uptake was significantly greater (-64%) than in histopathologic non-responders (-37%), (p=0.005). Using a 50% decrease in tumor SUV as a threshold value resulted in a sensitivity of 90% and a specificity of 58% for assessment of histopathologic response (p=0.01). Response assessment per RECIST showed no significant correlation with histopathologic response (sensitivity 20%, specificity 89%, p=0.4). There was no correlation between changes in tumor size and histopathologic response (area under the ROC curve = 0.6, p=0.1). Conclusions: In patients with high grade STS, quantitative FDG-PET was significantly more accurate than size based criteria for assessment of histopathologic response to neoadjuvant therapy. FDG-PET should be considered as a modality to monitor treatment response is patients with high grade STS.

No significant financial relationships to disclose.
Genomic of circulating tumor cells in metastatic breast cancer
Authors: Reuben J. M. , Lee B. N. , Li C. , Broglio K. R. , Valero V. , Jackson S. , Ueno N. T. , Krishnamurthy S. , Hortobagyi G. N. , Cristofanilli M.
Published: March 2020

1002

Background: Metastatic breast cancer (MBC) is an incurable condition and palliative treatments are selected by considering pre-treatment prognostic and predictive factors. Recently, we reported the detection of CTCs to be predictive of prognosis and treatment efficacy and reasoned they might also be used to assess biological characteristics of the patient’s tumor to improve on treatment selection. Methods: Twenty patients with newly diagnosed MBC were enrolled in a prospective clinical trial designed to assess the baseline value of CTCs, evaluate the expression of selected genes in CTCs, and compare the expression of same biomarkers in the primary tumor (PT) and/or metastatic site (MS), as determined by standard IHC and FISH. CTCs were assessed by CellSearch, and subjected to real-time PCR (qPCR) for the expression of transcripts for estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor (HER-2), notch-1, and mammaglobin (MGB) using commercial primers. Results: Sixteen of patients had =1CTCs. With respect to biomarkers of PT, 17 were ER+, 11 PR+, and 3 HER-2 amplified. Among the 15 patients with MS, the biomarkers were as follows: 9 ER+, 7 PR+, and 2 HER-2 amplified. There were significant associations between the primary and metastatic tumors with respect to the presence of ER (χ2 = 6.516, P = 0.0107), PR (χ2 = 5.529, P = 0.0187), and HER-2 (χ2 = 3.938, P = 0.0472). The qPCR of CTCs detected transcripts: ER in 3 patients (15%); PR in none (0%); MGB and HER-2 in 2 (10%) and 11 patients (55%), respectively. Notch-1 transcripts were detected in 13 patients (65%). CTCs with detectable transcripts of HER-2 were more likely to co-express notch-1 transcripts (χ2 = 4.295, P = 0.038). Of the 4 samples without detectable CTCs, one was HER-2 positive, and three had notch- 1 transcripts. Conclusions: This study demonstrated a significant concordance in biomarkers expression between the tumor cells of the primary tumors and the metastatic site. Furthermore, it suggests that CTCs differ significantly from those tumor cells with regards to the expression of hormone-receptor and HER-2 status. Thus, CTCs may represent a unique and heterogeneous cell population which phenotype and “homing” properties should be further investigated.

[Table: see text]
Inhibition of the Heat Shock Protein 90 (Hsp90) chaperone with the novel agent IPI-504 to overcome resistance to tyrosine kinase inhibitors (TKIs) in metastatic GIST: Updated results of a phase I trial
Authors: Demetri G. D. , George S. , Morgan J. A. , Wagner A. , Quigley M. T. , Polson K. , Pokela J. , van den Abbeele A. , Adams J. , Grayzel D.
Published: March 2020

10024

Background: Prior work from our team demonstrates that inhibition of the Hsp90 chaperone protein results in preferential destruction of the mutated KIT kinase in human GIST cell lines regardless of TKI-resistance mutations. To translate this into clinical application, we are conducting a phase I trial of IPI-504, a novel Hsp90 inhibitor, for patients (pts) with metastatic TKI-resistant GIST. Methods: Pts with metastatic TKI-resistant GIST were eligible to enter and receive IPI-504, IV in 250 cc of normal saline over 30 mins, on days 1, 4, 8 and 11 of a 21 day cycle. Serial monitoring with 18FDG-PET/CT imaging at baseline, day 11, and day 21, as well as PK profiling of IPI- 504 and its major active metabolites (17-AAG and 17-AG), were performed on all pts. Results: 21 pts with progressive GIST after both prior imatinib and sunitinib have been entered at 5 dose levels (90 mg/m2 IPI-504 [n=6], 150 [3], 225 [3], 300 [3], 400 [6]); 18 are now evaluable. The maximal tolerated dose has not been reached, and enrollment is ongoing. AEs possibly related to IPI-504 include Grade 1–2 elevation of alkaline phosphatase, fatigue, and headache; one DLT was observed in the 1st and 5th dose levels. PET demonstrated decreases in tumor FDG avidity in 1/6 pts, 1/3, 3/3, 1/3, and 2/3 at the respective dose levels in this schedule (3 patients were inevaluable by PET). Reactivation of tumor FDG uptake by PET was seen during the planned 10-day breaks in IPI-504 administration with reinduction of decreased tumor FDG avidity upon re-treatment with IPI-504. Although no RECIST-defined “anatomic responses” were noted, stable disease has allowed 7 pts to continue on study treatment for ≥ 4 cycles. Conclusions: Targeting Hsp90 is a novel therapeutic strategy in TKI-resistant GIST. IPI-504 has been well-tolerated overall, and the activity seen with decreased FDG avidity of GIST lesions, as well as the induction of SD in pts with documented prior progression, is promising with this non-TKI agent. Reactivation of PET signal in lesions during breaks in IPI-504 dosing is similar to flares with TKI discontinuation. To address this, a new schedule of continuous BIW dosing of IPI-504 has been added to optimize drug exposure.

No significant financial relationships to disclose.
Immunohistochemical expression of ezrin correlates with Event-free and overall survival in osteosarcomas
Authors: Salas S. , Deville J. , Bartoli C. , Gaudart J. , Bollini G. , Curvale G. , Gentet J. , Duffaud F. , Figarella-Branger D. , Bouvier C.
Published: March 2020

10035

Background: Ezrin is a cytoskeleton linker protein that is actively involved in the metastatic process of cancer cells. We have searched for a pronostic value of ezrin and some of its partners: a-smooth actin and CD44H in 37 patients with an osteosarcoma. Methods: Automate immunohistochemistry (IHC) with anti-ezrin, a-smooth actin and CD44H antibodies was performed in 37 biopsies before chemotherapy, 16 resected tumors of “poor” responders and 13 metastases. In addition the mRNA levels of ezrin of 13 frozen biopies and 4 metastases were evaluated by real time quantitative RT PCR. All results were correlated to the following clinical data: response to chemotherapy, onset of metastasis, event-free survival (EFS) and overall survival (OS). Results: Ezrin expression by IHC was found in 62% of 37 biopsies in the different histological subtypes especially chondroblastic osteosarcomas while chondrosarcomas were negative. A good correlation was found between positive or negative samples by IHC and mRNA levels. Ezrin expression was recorded in 84.5% of metastastic samples. The mean expression of ezrin was higher in metastases than biopsies (mean expression 38.1% versus 17.32%; p=0.024) but the onset of metastasis was not statistically correlated to ezrin positivity on biopsy (p = 0.183). In multivariate analysis, ezrin was an independent prognostic marker for EFS and OS with p<0.001 and p=0.003 respectively and a-smooth actin for OS only (p=0.024). No prognostic value was found for CD44H. Conclusions: We have shown that ezrin is expressed in the different subtypes of osteosarcomas especially chondroblastic osteosarcomas. Other studies are required to confirm that ezrin could be a useful tool for differential diagnosis with chondrosarcoma. Ezrin was an independent prognostic factor for event-free and overall survival rate in multivariate analysis and its partner a-smooth-actin was also an independent prognostic factor for overall survival only. These data confirm the role of ezrin signalling pathway for tumor dissemination in osteosarcomas in vivo. This also might be of interest for therapeutic strategy to select patient for dose intensification or to use new anticancer agents such as rapamycin which reduces experimental lung metastases through an ezrin-related pathway.

No significant financial relationships to disclose.
Expression of cell cycle, angiogenesis and metastases associated factors in osteosarcoma - immunohistochemical analysis of tissue array in 35 patients
Authors: Chen W. , He M. , Aisner S. , Benevenia J. , Patterson F. , Hameed M.
Published: March 2020

10036

Background: Osteosarcoma is the most common, non-haemopoietic primary malignant tumor of bone. A variety of biological markers have been investigated for their prognostic value with variable results. This study is aimed to assess the prognostic and biological value of biological markers involved in cell cycle checkpoint regulation (p53 family, p16, and PTEN), cell adhesion, motility and invasion (ezrin and beta catenin), angiogenesis (VEGF and PlGF) in tumor samples of osteosarcoma patients. Methods: Thirty-five patients were chosen for the study (ages 6–74 years, median age - 15 years). Among them, 32 were high-grade conventional intramedullary osteosarcoma, and 3 were Paget osteosarcomas. Eight patients presented with metastases. Immunohistochemical analysis was performed on a tissue array of tumor samples with standard protocol. Clinical outcome was measured as events (metastasis or death), chemo-response (stage), and survival by multivariate analysis. Analysis also included our previous reported results of p53, p63 and p73. Results: Staining was assessed based upon semi-quantitative manual scoring. Appropriate staining (nuclear or cytoplasmic) of >5% in tumor cells was considered as positive for all markers. The percentage positivity for the markers is as follows: p53 =29%, p63 =37%, p73= 9%, p16 =60%, PTEN=83%, ezrin =77%, beta catenin =91%, VEGF= 86% and PlGF =54%. There was no association of marker expression with specific subtype or location. Statistical analysis revealed no significant association between the positivity of these markers with clinical outcomes. Expression of ezrin was observed in all eight patients with metastases, although this finding did not approach statistical significance (P = 0.15). There was significant association between ezrin and P63 (P < 0.05). Conclusions: 1. Expression of p53 family proteins, p16, PTEN, ezrin, beta catenin, VEGF, and PlGF are not significant predictors of clinical outcome in osteosarcoma patients. 2. Ezrin may be essential for osteosarcoma metastases. 3. No significant association between VEGF, PlGF and metastases. 4. The positive association between ezrin and P63 is interesting and need to be evaluated further.

No significant financial relationships to disclose.
Trabectedin (T) in metastatic Ewing's family tumors (EFT) patients (pts) progressing after standard chemotherapy
Authors: Dileo P. , Grosso F. , Casanova M. , Jimeno J. , Marsoni S. , Sanfilippo R. , Podda M. , Ferrari S. , Bertulli R. , Casali P. G.
Published: March 2020

10040

Background: T is a formerly marine-derived agent which is active in human cancers, such as ovarian cancer and adult soft tissue sarcomas (STS). Efficacy of T in pts with unresectable/metastatic pretreated advanced STS was demonstrated in phase II settings. Leiomyosarcoma and liposarcoma were shown to be sensitive, with myxoid liposarcoma being exceedingly responsive. Data are lacking on “small round blue cell” sarcomas, including EFT. In 2000 a phase II study was launched by SENDO in a sarcoma population including EFT. At Istituto Nazionale Tumori, Milano, Italy, some EFT pts were treated after the completion of this study. We analyzed treatment efficacy in EFT pts treated within these two settings. Methods: Overall 15/29 of the pts were female, and age ranged from 15 to 55 years. Pts received T at a starting dose between 1,650 and 1,100 mcg/sqm every 3 weeks as 24-hour or 3-hour infusion. Each pt received at least 2 cycles of treatment, except in case of disease progression or unacceptable toxicity. Tumor response was assessed by RECIST criteria after the first 2 cycles and then every other cycle. Dose reductions were based on the worst toxicity (hematological or non-hematological) in the previous cycle. Results: As of December 2006, 20 pts were treated in the Phase II study, and 9 on a compassionate use basis. Two pts were still on therapy. A total of 79 treatment cycles (2–14 per pt) were administered. Three pts (10.3%) demonstrated a partial response, 3 had a minor response (10.3%), and 4 (13.7%) stable disease. PFS rate at 6 months was 25%. The most common all-causality AEs were acute reversible liver toxicity, fatigue, and myelosuppression. Following the introduction of steroid pre-medication, thrombocytopenia and fatigue were less frequent. Conclusions: In this cohort, T was overall well tolerated and showed antitumor activity in pts with advanced EFT. This calls for further evaluation of this compound, alone or in combination, in pts suffering from EFT.

No significant financial relationships to disclose.