bluuebunny/crossref_metadata_2025_split huggingface dataset:
PRISM protocol: a randomised phase II trial of nivolumab in combination with alternatively scheduled ipilimumab in first-line treatment of patients with advanced or metastatic renal cell carcinoma
Authors: Buckley Hannah L. , Collinson Fiona J. , Ainsworth Gemma , Poad Heather , Flanagan Louise , Katona Eszter , Howard Helen C. , Murden Geraldine , Banks Rosamonde E. , Brown Joanne , Velikova Galina , Waddell Tom , Fife Kate , Nathan Paul D. , Larkin James , Powles Thomas , Brown Sarah R. , Vasudev Naveen S. 
Published: November 2019

Abstract
Background
The combination of nivolumab, a programmed death-1 (PD-1) targeted monoclonal antibody, with the cytotoxic T-lymphocyte antigen-4 (CTLA-4) targeted antibody, ipilimumab, represents a new standard of care in the first-line setting for patients with intermediate- and poor-risk metastatic renal cell carcinoma (mRCC) based on recent phase III data. Combining ipilimumab with nivolumab increases rates of grade 3 and 4 toxicity compared with nivolumab alone, and the optimal scheduling of these agents when used together remains unknown. The aim of the PRISM study is to assess whether less frequent dosing of ipilimumab (12-weekly versus 3-weekly), in combination with nivolumab, is associated with a favourable toxicity profile without adversely impacting efficacy.

Methods
The PRISM trial is a UK-based, open label, multi-centre, phase II, randomised controlled trial. The trial population consists of patients with untreated locally advanced or metastatic clear cell RCC, and aims to recruit 189 participants. Participants will be randomised on a 2:1 basis in favour of a modified schedule of 4 doses of 12-weekly ipilimumab versus a standard schedule of 4 doses of 3-weekly ipilimumab, both in combination with standard nivolumab. The proportion of participants experiencing a grade 3 or 4 adverse reaction within 12 months forms the primary endpoint of the study, but with 12-month progression free survival a key secondary endpoint. The incidence of all adverse events, discontinuation rates, overall response rate, duration of response, overall survival rates and health related quality of life will also be analysed as secondary endpoints. In addition, the potential of circulating and tissue-based biomarkers as predictors of therapy response will be explored.

Discussion
The combination of nivolumab with ipilimumab is active in patients with mRCC. Modifying the frequency of ipilimumab dosing may mitigate toxicity rates and positively impact quality of life without compromising efficacy, a hypothesis being explored in other tumour types such as non-small cell lung cancer. The best way to give this combination to patients with mRCC must be similarly established.

Trial registration
PRISM is registered with ISRCTN (reference ISRCTN95351638, 19/12/2017).

Trial status
At the time of submission, PRISM is open to recruitment and data collection is ongoing.
Incidence of atrial fibrillation in different major cancer subtypes: a Nationwide population-based 12 year follow up study
Authors: Jakobsen Christina Boegh , Lamberts Morten , Carlson Nicholas , Lock-Hansen Morten , Torp-Pedersen Christian , Gislason Gunnar H. , Schou Morten 
Published: November 2019

Abstract
Background
The prevalence of both atrial fibrillation (AF) and malignancies are increasing in the elderly, but incidences of new onset AF in different cancer subtypes are not well described.The objectives of this study were therefore to determine the incidence of AF in different cancer subtypes and to examine the association of cancer and future AF.

Methods
Using national databases, the Danish general population was followed from 2000 until 2012. Every individual aged > 18 years and with no history of cancer or AF prior to study start was included. Incidence rates of new onset AF were identified and incidence rate ratios (IRRs) of AF in cancer patients were calculated in an adjusted Poisson regression model.

Results
A total of 4,324,545 individuals were included in the study. Cancer was diagnosed in 316,040 patients. The median age of the cancer population was 67.0 year and 51.5% were females. Incidences of AF were increased in all subtypes of cancer. For overall cancer, the incidence was 17.4 per 1000 person years (PY) vs 3.7 per 1000 PY in the general population and the difference increased with age. The covariate adjusted IRR for AF in overall cancer was 1.46 (95% confidence interval (CI) 1.44–1.48). The strength of the association declined with time from cancer diagnosis (IRR0-90days = 3.41 (3.29–3.54), (IRR-180 days-1 year = 1.57 (CI 1.50–1.64) and (IRR2–5 years = 1.12 (CI 1.09–1.15).

Conclusions
In this nationwide cohort study we observed that all major cancer subtypes were associated with an increased incidence of AF. Further, cancer and AF might be independently associated.
Mapping of sentinel lymph node drainage using SPECT/CT to tailor elective nodal irradiation in head and neck cancer patients (SUSPECT-2): a single-center prospective trial
Authors: de Veij Mestdagh Pieter D. , Schreuder Willem H. , Vogel Wouter V. , Donswijk Maarten L. , van Werkhoven Eric , van der Wal Jacqueline E. , Dirven Richard , Karakullukcu Baris , Sonke Jan-Jakob , van den Brekel Michiel W. M. , Marijnen Corrie A. M. , Al-Mamgani Abrahim 
Published: November 2019

Abstract
Background
The majority of patients with head and neck squamous cell carcinoma (HNSCC) receive bilateral elective nodal irradiation (ENI), in order to reduce the risk of regional failure. Bilateral ENI, as compared to unilateral ENI, is associated with higher incidence of acute and late radiation-induced toxicity with subsequent deterioration of quality of life. Increasing evidence that the incidence of contralateral regional failure (cRF) in lateralized HNSCC is very low (< 10%) suggests that it can be justified to treat selected patients unilaterally. This trial aims to minimize the proportion of patients that undergo bilateral ENI, by using lymph drainage mapping by SPECT/CT to select patients with a minimal risk of contralateral nodal failure for unilateral elective nodal irradiation.

Methods
In this one-armed, single-center prospective trial, patients with primary T1-4 N0-2b HNSCC of the oral cavity, oropharynx, larynx (except T1 glottic) or hypopharynx, not extending beyond the midline and planned for primary (chemo) radiotherapy, are eligible. After 99mTc-nanocolloid tracer injection in and around the tumor, lymphatic drainage is visualized using SPECT/CT. In case of contralateral lymph drainage, a contralateral sentinel node procedure is performed on the same day. Patients without contralateral lymph drainage, and patients with contralateral drainage but without pathologic involvement of any removed contralateral sentinel nodes, receive unilateral ENI. Only when tumor cells are found in a contralateral sentinel node the patient will be treated with bilateral ENI. The primary endpoint is cumulative incidence of cRF at 1 and 2 years after treatment. Secondary endpoints are radiation-related toxicity and quality of life. The removed lymph nodes will be studied to determine the prevalence of occult metastatic disease in contralateral sentinel nodes.

Discussion
This single-center prospective trial aims to reduce the incidence and duration of radiation-related toxicities and improve quality of life of HNSCC patients, by using lymph drainage mapping by SPECT/CT to select patients with a minimal risk of contralateral nodal failure for unilateral elective nodal irradiation.

Trial registration
ClinicalTrials.gov Identifier: NCT03968679, date of registration: May 30, 2019.
Atypical ovarian carcinoid tumor with widespread skeletal metastases: a case report of multiple endocrine neoplasia type 1 in a young woman
Authors: Lou Lei , Zhou Lixia , Wang Wenyan , Li Huina , Li Yuehong 
Published: November 2019

Abstract
Background
Multiple endocrine neoplasia type 1 (MEN1) is a rare autosomal dominant inherited condition affecting multiple endocrine organs, resulting in significant morbidity and decreased life expectancy. Early tumor identification allows for timely patient management, reduces morbidity, and improves disease outcomes. Patients with MEN1 typically present with primary hyperparathyroidism caused by multiple parathyroid tumors, however, thymic and bronchial carcinoid tumors are also less common manifestations. MEN1-related neuroendocrine tumors often show hematogenous metastasis, with the liver being the most common metastatic site. Skeletal metastases from neuroendocrine tumors are extremely rare.
As few as 50 case reports were identified in a recently published literature review on skeletal metastases from carcinoid tumors. To our knowledge, studies related to MEN1 have not been previously conducted.

Case presentation
We present a case of MEN1-related atypical ovarian carcinoid presenting as the first disease manifestation in a 30-year old woman. After two years, another atypical carcinoid was incidentally diagnosed in the contralateral ovary during a caesarean section. Syndromic MEN1 was not diagnosed clinically despite her young age and bilateral involvement. The patient remained disease-free for two years without further adjuvant treatment prior to clinic presentation with complaints of chest discomfort and body pain. Radiologic and pathologic investigations identified multifocal simultaneous neuroendocrine tumors involving the parathyroid, thymus, pancreas, and adrenal glands, in addition to multiple other metastatic sites. The findings ultimately resulted in the patient being diagnosed with MEN1.

Conclusions
This extremely rare case emphasizes that ovarian carcinoids, especially when bilateral, could be the initial manifestation of MEN1. The significance of this differential diagnosis was highlighted by the subsequent detection of widespread skeletal metastasis resulting from the carcinoid tumors. A low threshold of suspicion, systemic diagnostic work-up, and regular follow-up are of utmost importance to timely diagnosis of MEN1.
Characterizing MRI features of rectal cancers with different KRAS status
Authors: Xu Yanyan , Xu Qiaoyu , Ma Yanhui , Duan Jianghui , Zhang Haibo , Liu Tongxi , Li Lu , Sun Hongliang , Shi Kaining , Xie Sheng , Wang Wu 
Published: November 2019

Abstract
Background
To investigate whether MRI findings, including texture analysis, can differentiate KRAS mutation status in rectal cancer.

Methods
Totally, 158 patients with pathologically proved rectal cancers and preoperative pelvic MRI examinations were enrolled. Patients were stratified into two groups: KRAS wild-type group (KRASwt group) and KRAS mutation group (KRASmt group) according to genomic DNA extraction analysis. MRI findings of rectal cancers (including texture features) and relevant clinical characteristics were statistically evaluated to identify the differences between the two groups. The independent samples t test or Mann-Whitney U test were used for continuous variables. The differences of the remaining categorical polytomous variables were analyzed using the Chi-square test or Fisher exact test. A receiver operating characteristic (ROC) curve analysis was performed to evaluate the discriminatory power of MRI features. The area under the ROC curve (AUC) and the optimal cut-off values were calculated using histopathology diagnosis as a reference; meanwhile, sensitivity and specificity were determined.

Results
Mean values of six texture parameters (Mean, Variance, Skewness, Entropy, gray-level nonuniformity, run-length nonuniformity) were significantly higher in KRASmt group compared to KRASwt group (p < 0.0001, respectively). The AUC values of texture features ranged from 0.703~0.813. In addition, higher T stage and lower ADC values were observed in the KRASmt group compared to KRASwt group (t = 7.086, p = 0.029; t = − 2.708, p = 0.008).

Conclusion
The MRI findings of rectal cancer, especially texture features, showed an encouraging value for identifying KRAS status.
Serum erythropoietin concentration and its correlation with stage of diabetic retinopathy
Authors: Davidović Sofija , Babić Nikola , Jovanović Sandra , Barišić Sava , Grković Desanka , Miljković Aleksandar 
Published: November 2019

Abstract
Background
Erythropoietin (EPO) is one of the systemic angiogenic factors, and its role in ocular angiogenesis and in diabetic retinopathy (DR) is not yet fully understood. The latest research data reveal a possible correlation of higher erythropoietin concentrations in the blood and in the eye with the development of more advanced stages of DR.
The main aim of this work was to examine the possible influence of serum concentrations of erythropoietin on the development of diabetic retinopathy in patients with diabetes mellitus type 2.

Methods
The research involved 90 patients examined at the University Eye Clinic of the Clinical Center of Vojvodina, Novi Sad, Serbia. The first group comprised 60 patients with diabetes mellitus lasting for 10 years or more, with diabetic retinopathy. The second, control group consisted of 30 healthy individuals. In the first group of 60 patients with diabetes, 30 of them had non-proliferative diabetic retinopathy (NPDR), and 30 had proliferative diabetic retinopathy (PDR). Laboratory EPO serum levels were determined, and they were correlated to the stage of DR. Concentration of EPO was assessed by ELISA method.

Results
The highest average concentration of EPO in serum (9.95 mIU/ml) was determined in the group of people with diabetes with PDR. The lowest average concentration of EPO in the serum (6.90 mIU/ml) was found in the control group. The average concentration of EPO in serum in the group of patients with diabetes with NPDR was 7.00 mIU/ml. The EPO concentration in serum was elevated in the group of PDR, and it was directly proportional to the level of the clinical stadium of PDR, being significantly higher in the moderate and severe subgroup of PDR comparing to the control healthy subjects, NPDR and mild PDR (p = 0.007).

Conclusions
Significantly elevated serum concentration of EPO in the advanced stages of DR, and positive correlation between EPO serum concentration and clinical stages of PDR, suggest that erythropoietin represents an important growth factor from blood, which plays a significant role in retinal ischemia and angiogenesis in diabetic retinopathy, especially in the proliferative stage of this disease.
Occupational social class trajectories in physical functioning among employed women from midlife to retirement
Authors: Lahelma Eero , Pietiläinen Olli , Chandola Tarani , Hyde Martin , Rahkonen Ossi , Lallukka Tea 
Published: November 2019

Abstract
Background
Prior analyses of class differences in health trajectories among employees have often omitted women and transitions to retirement. We examined social class trajectories in physical functioning among Finnish female employees from midlife to retirement age, and whether transitions to retirement modified these trajectories.

Methods
Data were derived from mail surveys at Phases 1–3 (2000–2012) among employees of the City of Helsinki, Finland, aged 40–60 at baseline (n = 8960, 80% women, response rates 69–83%). We included respondents to any of the Phases 1–3 aged 40–72 (n = 6976). We distinguished higher and lower social classes, and employment statuses, i.e. employed, mandatorily retired and disability-retired. Short Form 36 physical component summary was used to measure physical functioning. Mixed-effect growth curve models were used to assess the association of social class and employment status with functioning over age.

Results
For employed women, physical functioning deteriorated faster in the lower than in the higher class, with class trajectories widening in ages 40–65. After mandatory retirement, functioning deteriorated in both classes, whereas after disability retirement, functioning improved. Across employment statuses, functioning converged at older ages, and the disability-retired caught up with the better functioning of the employed and mandatorily retired. Employment status modified the trajectories, as among the continuously employed and mandatorily retired women functioning deteriorated, but among the disability-retired, trajectories improved and reached a similar level with employed and mandatorily retired women. Social class inequalities remained in all employment status groups.

Conclusions
Overall, our results suggest evidence for the cumulative disadvantage model, with accumulating work exposures among lower classes potentially contributing to their trajectories of ill health.
Moderating role of job satisfaction on turnover intention and burnout among workers in primary care institutions: a cross-sectional study
Authors: Chen Xuyu , Ran Li , Zhang Yuting , Yang Jinru , Yao Hui , Zhu Sirong , Tan Xiaodong 
Published: November 2019

AbstractBackgroundGlobal countries are suffering from a shortage of health professionals. Turnover intention is closely related to job satisfaction and burnout, making good use of these relationships could alleviate the crisis. Our research aims to examine the mediating role of job satisfaction in the relationship between burnout and turnover intention.MethodsThis research was conducted in Huangpi, China. The convenience sampling method and self-administereded questionnaires were used. 1370 of valid samples were collected with 97.72% effective rate. Descriptive analyses were conducted to describe social demographic factors. The structural equation model (SEM) was performed to adjust model fitting, and the mediation effect test was carried out by using the bootstrap method. Sobel-Z test was used to verify the significance of mediation effect.ResultsThe mean age was 36.98 (SD = 9.84). The fitting indices of hypothetical model are not good. After the adjustments,χ2/df = 5.590, GFI = 0.932, AGFI = 0.901, CFI = 0.977, NFI = 0.973, IFI = 0.977, TLI = 0.970, RESEA = 0.058. The revised model fitted well, and the SEM was put up by using the bootstrap method. The mediating effect is partial, and Soble-Z test indicates that the mediation effect is significant. Burnout is negatively correlated with job satisfaction (p < 0.01) and the standardized path coefficient is − 0.41. Job satisfaction is also negatively correlated with turnover intention (p < 0.01) and the standardized path coefficient is − 0.18. Burnout is positively correlated with turnover intention (p < 0.01) and the standardized path coefficient is 0.83.ConclusionsJob satisfaction is a mediating variable that affects the relationship between burnout and turnover intention. The mediating effect was a partial mediating effect and has a low impact of 7.4%. Improving treatment and giving more promotion opportunities for workers to improve job satisfaction, conducting career planning course and paying attention to employee psychological health to reduce job burnout. The above measures may be helpful to reduce employee turnover rate and alleviating the current situation of a shortage of health personnel in China.
Adiposity and changes in movement-related behaviors in older adult women in the context of the built environment: a protocol for a prospective cohort study
Authors: Cuberek Roman , Pelclová Jana , Gába Aleš , Pechová Jana , Svozilová Zuzana , Přidalová Miroslava , Štefelová Nikola , Hron Karel 
Published: November 2019

AbstractBackgroundIn older adults, sedentary behaviors increase while physical activity decreases over time following the compositional nature of 24-h behaviors. These changes in movement-related behaviors (MRBs) might be associated with unhealthy weight gain and several health comorbidities. However, information is lacking on how obesity influences longitudinal changes in the composition of MRBs in older adults. Furthermore, the moderating effect of the built environment on prospective associations between obesity and MRBs in older adults is not fully understood. Therefore, using an integrated time-use approach, this study aims to identify prospective associations between obesity and MRBs together with an assessment of the moderating effect of the built environment in elderly women.MethodsThe study was designed as a prospective 7-year follow-up study. It is based on two previous cross-sectional studies that enable the use of participant data (women aged 60+ years,n = 409) as a baseline dataset in the current study. All methods designed for 7-year follow-up are based on previous studies. The data collection comprises device-based measurement of MRBs (ActiGraph GT1M accelerometer), objective assessment of body adiposity (multi-frequency bioelectrical impedance analysis), subjective assessment of the built environment (NEWS-A questionnaire), and other possible confounding factors. Time spent in sedentary behavior, light physical activity, and moderate-to-vigorous physical activity will be used as three components in a composition reflecting individual MRBs. In linear multiple compositional regression analysis assessing the prospective association between obesity and MRBs, the 7-year follow-up composition of the three mentioned components represents the dependent variable. The 7-year changes in the percentage of body fat (body adiposity), baseline composition of MRBs, and parameters of the built environment represent regressors.DiscussionThis study will use an integrated time-use approach to explore causality from obesity to device-measured behaviors in older women. The design and respective analysis consider the compositional nature of MRBs data and the potential moderating effects of various factors. A comprehensive assessment of causality may help to develop multilevel interventional models that enhance physical activity in older adults.
The effects of deep neck muscle-specific training versus general exercises on deep neck muscle thickness, pain and disability in patients with chronic non-specific neck pain: protocol for a randomized clinical trial (RCT)
Authors: Kashfi Pegah , Karimi Noureddin , Peolsson Anneli , Rahnama Leila 
Published: November 2019

AbstractBackgroundAltered thickness, cross-sectional area and activity of deep neck muscles have frequently been reported in patients with chronic non-specific neck pain (CNNP). It is claimed that these muscles do not recover spontaneously. These muscles provide a considerable amount of cervical stability. Therefore, various therapeutic exercises have been recommended to recover from resulting complications. However, most exercise protocols do not target deep neck muscles directly. Thus, this might be a reason for long-lasting complications. Accordingly, the purpose of the present study is to discuss a randomized controlled trial (RCT) protocol in which we aim to investigate and compare the effects of neck-specific exercise programmes versus general exercise programmes in patients with CNNP.MethodsA 2*2 factorial RCT with before-after design. Sixty-four participants with CNNP will be recruited into the study. They will be randomly divided into two groups, including specific neck exercise and general exercise. Each exercise programme will be carried out three times a week and will last for 8 weeks. Primarily, dorsal and ventral neck muscle thickness, pain and disability and secondarily, muscle strength, quality of life, sleep quality, fear avoidance and neck range of motion will be assessed at the baseline and immediately at the end of the exercise protocol.DiscussionThe results of this study will inform clinicians on which type of exercise is more beneficial for patients with CNNP.Trial registrationIRCT2017091620787N2, Sep 16 2017.