bluuebunny/crossref_metadata_2025_split huggingface dataset:
Establishing a health economics and value unit at the Children’s Cancer Hospital–Egypt: Introducing a practical approach for evidence-based decision making.
Authors: Soliman Ranin , Tarek Nourhan , Samir Sandra , Okail Shimaa , Eweida Wael , Abouelnaga Sherif 
Published: June 2021

e18859 Background: Health Economics is a multi-disciplinary practice that recently gained recognition in healthcare management systems. Value-based healthcare (VBHC) focuses on improving patient outcomes while using fewer healthcare resources. Integrating the principles of health economics and VBHC are essential to better inform decision-making based on evidence, especially in resource-limited settings, that need ultimate efficiency in managing resources. Egypt has the highest second estimated number of incident childhood cancer cases in the Eastern Mediterranean Region (EMR), based on GLOBOCAN 2020. Thus, childhood cancer in Egypt is an urging priority due to the large number of patients, limited resources, and poor outcomes. There is a need to optimize resource use and promote value in care delivery for childhood cancer care in Egypt, based on real-world evidence. Methods: This work aims to highlight the role of establishing a health economics and value (HEV) unit at the Children’s Cancer Hospital 57357 –Egypt (CCHE), to improve care and outcomes for children with cancer efficiently. CCHE is a not-for profit pediatric oncology center, treating around 50–60% of childhood cancers across Egypt free of charge. Results: The HEV unit was established in 2017 as a sub-function of the upper management at the hospital. The core mission of the unit is to translate health economics and VBHC concepts into practice to promote evidence-based decision-making, through applying the following functions and activities: monitoring trends in childhood cancer survival, resource use, and costs; applying health economic evaluation tools such as cost-effectiveness analysis (CEA) and multi-criteria decision analysis (MCDA); applying time-driven activity based costing (TDABC); implementing VBHC on a disease- and a hospital-level; monitoring costs and benchmarking. Some of these functions/activities reflect on operational processes such as integrating the CEA tools within the hospital procedures to maximize value of money spent; and restructuring hospital-wide cost centers for accurate costs reporting. Capacity building is also an important pillar in the unit’s framework, where the unit team conducts internal and external training sessions and workshops to spread the knowledge about health economics, VBHC, and evidence-based healthcare. Conclusions: The HEV unit at CCHE presents a unique model of applying health economics and value-based healthcare at a micro level in a pediatric oncology center in Egypt. This is a novel approach for healthcare management in Egypt and making informed decisions based on real-world evidence.
Co-occurring alteration of NOTCH and DDR pathways serve as novel predictor to efficacious immunotherapy in NSCLC.
Authors: Zhang Zhimin , Gu Yanyan , Su Xiaona , Bai Jing , Guan Wei , Ma Jungang , Luo Jia , He Juan , Zhang Bicheng , Geng Mingying , Xia Xuefeng , Guan Yan-Fang , Shen Cheng , Chen Chuan 
Published: June 2021

e21106 Background: Although immune checkpoint inhibitors (ICIs) have shown remarkable benefit for treatment of advanced non-small lung cancer (NSCLC), only a minority of patients can achieve durable responses and the majority produce an ultra-rapid progressive disease. Methods: Here, we collected the availably published datasets and mined the determinants of response to immunotherapy on pathway levels. 106 NSCLC patients treated with immunotherapy were combined from Rizvi et. al and Hellman et. al studies (whole exon sequencing) as the discovery dataset. Two independent validation datasets were comprised of the MSKCC cohort (targeted sequencing) and data by Anagnostou and colleagues (whole exon sequencing). The Cancer Genome Atlas (TCGA) somatic mutation and gene expression data were applied to explore the immunobiology features. Results: In the first combined cohort, we detected NOTCH pathway altered in 71% patients with durable clinical benefit (DCB) while only 36% among no durable benefit (NDB) (p = 0.005). Compared to NDB group, co-occurrence of NOTCH and at least two DDR (co-DDR) pathway was discovered in DCB group and contributed to a prolonged progression-free survival (PFS) [ 22.1 vs 3.6 months, p < 0.0001, HR, 0.34, 95% confidence interval (CI), 0.2-0.59]. In two independent datasets, co-occurrence of NOTCH+/co-DDR+ was also validated to be a better immunotherapy efficacy [ Cohort 2: 13 vs 6 months, p = 0.034, HR, 0.55, 95% CI, 0.31-0.96 ; Cohort 3: 21 vs 11 months, p = 0.067, HR, 0.45, 95% CI, 0.18-1.1 ]. By analyzing TCGA cohort, we found patients with coexisting NOTCH and co-DDR pathway had a higher TMB, more infiltration of CD4+T cells. Conclusions: Overall, co-occurrence of NOTCH and co-DDR pathway reflect a better immunotherapy efficacy in advanced NSCLC. This genomic predictor show promise in stratifying patients that suit for immunotherapy for future clinical practice.
Genomic analysis of primary malignant melanoma of the esophagus.
Authors: Li Jingjing , Yan Shi , Guan Wenyan , Xiao Xiao , Liu Bing , Wang Changxi , Yu Zicheng , Ma Yuanyuan , Wu Nan 
Published: June 2021

e21515 Background: Primary malignant melanoma of the esophagus (PMME) is an exceedingly rare disease but behave more aggressively and have a poorer prognosis. No specific histopathological classification and therapy strategies have been established for this type of disease due to lack of both tumor biological and genetics perception to PMME. Methods: We performed whole exome sequencing on 29 dissections including 23 primary tumors and 6 metastatic lymph nodes from 18 PMME patients. The genetic characteristics including somatic mutations and copy number variation (CNV) of PMME were compared to 398 skin cutaneous melanoma (SKCM), 67 mucosal melanoma (MM) and 79 uveal melanoma (UVM). Using multi-region sequencing, we reconstructed the phylogenetic structure and inferred the evolutionary mode. Results: We found that PMME/MM have similar genomic patterns to SKCM but distinct from UVM. Frequently mutated driver genes such as MUC16, BRAF, NRAS, NF1, KMT2C, POLE, PTPRT, RANBP2 appeared in both SKCM and PMME/MM cohorts. Of note, pathway enrichment analysis using identified driver genes revealed that melanoma pathway and MAPK signaling pathway were among the top affected pathways in MM/PMME as well as in SKCM. UVR-associated single base substitution signature 7 (SBS7) was not a dominant signature (median: 0.17, range:0̃0.79) in PMME/MM but 99 percent (89/90) of them do have it. An overall concordant trend in genome instability was found between PMME and SKCM. Significant CNV events at arm level showed the similar changes in PMME and SKCM, including amplification regions of 1q, 6p, 7p, 8q, 15q, 20p and deletion of 10p, 10q, 11p. CDKN2A loss appeared as a shared focal event by PMME and SKCM. To elucidate the evolution trajectory of spatially separated samples, we also performed multi-region sequencing, and the phylogenetic analysis suggested that whole genome doubling (WGD) was an early and clonal event, which preceded the majority of somatic mutations and CNV. Most driver genes such as NF1, RANBP2 and MUC16 mutated after WGD except TP53. Above findings suggested that WGD might be capable of promoting ongoing genome instability and shaping the evolution in PMME. Moreover, parallel evolution of RANBP2 was recurrently observed indicating the existence of constraints and selection. Conclusions: Our data showed that PMME/MM exhibited genetic features very similar to SKCM so it might not be excluded from treatments currently used for common SKCM.
Metastatic site-specific utilization and outcome of immunotherapy in stage IV melanoma: A national perspective.
Authors: Cao Lifen , Bliggenstorfer Jonathan T. , Towe Christopher W. , Mangla Ankit , Miller Megan E. , Rothermel Luke 
Published: June 2021

e21525 Background: Metastatic melanoma is an aggressive disease with a rapid systemic dissemination. We evaluated the effect of metastatic sites on the utilization immunotherapy and survival outcomes in stage IV melanoma. Methods: The National Cancer Database from 2010-2017 was queried for stage IV melanoma. Those with missing relevant data were excluded. Patients were grouped into five categories based on metastatic sites: lung metastasis only, brain metastasis only, liver metastasis only, bone metastasis only and multiple sites metastasis. Multivariable logistic regression was used to predict use of immunotherapy. Effects of immunotherapy on overall survival were assessed using Kaplan-Meier curves and Cox proportional hazards model. Results: A total 12, 315 were included in the study, among whom 2206 (17.9%) had lung metastasis only, 1,873 (15.2%) had brain metastasis only, 785 (6.4%) had liver metastasis only, 662 (5.4%) had bone metastasis only and 5,983 (48.6%) presented with multiple metastatic sites. Surgery at primary site was performed in 34.3% of patients with bone metastasis (p<0.001), and radiation therapy was delivered to 69.2% patients with brain metastasis (p<0.001). Site of metastatic disease was associated with immunotherapy utilization, with multiple sites (OR = 1.149, p=0.012), and distant lymph nodes (OR=2.867, p<0.001) demonstrating the strongest association, while patients with oligo brain metastasis were less likely to receive immunotherapy (OR = 0.486, p<0.001). Immunotherapy is associated with superior survival among metastatic melanoma patients (HR=0.433, P<0.001). The Kaplan-Meier curves showed the median overall survival among the immunotherapy group was 33.7 months for lung metastasis (vs. 13.4 months without immunotherapy, HR=0.633, p<0.001), 25 months for brain metastasis (vs. 6.7 months without immunotherapy, HR=0.447, P<0.001), 16.8 months for liver metastasis (vs. 4.2 months without immunotherapy, HR=0.449, P<0.001), 18.3 months in bone metastasis (vs. 7.6 months without immunotherapy, HR=0.615, p<0.001) and 12.1 months in multiple metastasis (vs. 3.8 months without immunotherapy, HR=0.338, p<0.001). Conclusions: Utilization of immunotherapy is influenced by location of metastatic disease in stage IV melanoma. Overall survival is improved for patients treated with immunotherapy.[Table: see text]
Analysis of metastatic melanoma treated with immune checkpoint inhibitors and the rates of adverse events of colitis and hepatitis.
Authors: Horan Emily , Arneil Melissa , Xu Wen , Atkinson Victoria 
Published: June 2021

e21591 Background: Immune checkpoint inhibitors (CPI) are widely used in metastatic melanoma (MM), where it has markedly improved survival outcomes. ICI induced autoimmune adverse reactions (irAE) manifest in all organ systems and are due to over-activation of the immune system. Clinically relevant irAE are colitis and hepatitis as drivers of morbidity and mortality. Methods: Data was collected from a single centre (Princess Alexandra Hospital) from the electronic medical records system and immunotherapy prescribing software. Patient demographics, treatments, complications and outcomes were recorded from 2016-2019. Eligible patients had to have received immunotherapy (pembrolizumab, ipilimumab, or nivolumab) and experienced colitis or hepatitis toxicity. Trial patients were excluded. Results: The cohort of 337 patients who had received immune therapy, 18% (n = 61) had hepatitis or colitis, mean age was 56 years, 64% male. The majority were stage 4d 28% (n = 17). Braf wildtype accounted for 56% (n = 34). The highest rates of irAE occurred on combination ipilimumab and nivolumab 56% (n = 34), 10% nivolumab (n = 6), 3% (n = 2) ipilimumab, and 31% (n = 19) pembrolizumab monotherapy. Colitis affected 61% of patients (n = 37), 30% (n = 18) were grade 3 severity. Hepatitis affected 48% (n = 29), 18% (n = 32) were grade 1. The majority required oral steroids (80%, n = 49), followed by intravenous steroids (51%, n = 31), infliximab (18%, n = 11) and mycophenolate in 5% (n = 3). Hospitalisation occurred in 56% (n = 34), 20% (n = 12) requiring treatment cessation. Progressive disease occurred in 62% (n = 38), and 13% (n = 8) had a complete response. Conclusions: The findings of this analysis mirror current literature with immunotherapies used, rates and severity of irAE. The management of irAE also aligned with current guidelines. Further research is required to investigate patient factors increasing the risk of developing irAE, and ideal treatment regimens. Analysing this large cohort, the incidence of toxicity was 17%, predominantly colitis followed by hepatitis. Patients were severely impacted requiring significant interventions to manage toxicity, hospitalisation and morbidity.
An oncopalliative expertise unit in a French comprehensive cancer center: Experience at one year.
Authors: Mateus Christine , Vigouret-Viant Laurence , Voisin Sabine , Laurent Sophie , Renard Perrine , Sampetrean Anda , Pavliuc Elena , Scotte Florian , Dauchy Sarah 
Published: June 2021

e24077 Background: Anticipation of palliative care improves advanced cancer patients quality of life and may increase survival. It has also been associated with health costs reduction. However it is made difficult by societal taboos and reluctance of patients and caregivers to talk about therapeutic limitations and end of life. Methods: In a large French Comprehensive Cancer Center (CCC), the causes for both emergency consultations and medical hospitalizations have been analyzed, showing that repeated hospitalizations are more frequent when the level of care complexity increases and when the therapeutic project is unclear. Considering the European and international experiences of acute palliative care unit (APCU), we decided to create an APCU with reinforced onco-palliative expertise. This Onco-Palliative Expertise Unit (OPEU) main objective, besides treating refractory symptoms is to allow oncologists, palliative care specialists, pts and relatives to discuss together in order to redefine the therapeutic project. Results: One year after opening, this 10-bed unit has received 251 patients in 314 stays. 53% came directly from the home, 46% were already being followed by our palliative care team. After an average length of stay of 11.6 days, discharge was distributed between return home (41%), a palliative care unit (26%), death (22%) and other oncology units, or other hospitals (11%). At the opening, refractory symptoms were the most frequent reason for hospitalization (67% of stays). For the first 6 months period to the second one, discussing the therapeutic project increased from 23% to 34% of the hospitalization causes in the OPEU, showing the appropriation of this unit by the oncologists. A discussion about the project was carried out for almost all stays. On admission, specific cancer treatment was ongoing for 56% of stays. After assessment and multidisciplinary discussion, 49% of them decided to stop chemotherapy. Conversely, the start or resumption of treatment was recommended for 9% of stays without specific treatment on admission. The OPEU is a decompression chamber in the pt care pathway, which allows a multidisciplinary analysis of the pt’s condition on a single unit and leads to a quick and more appropriate therapeutic decision. Of the 251 pts hospitalized, only 19% were readmitted to hospital during the same one-year period, mainly for refractory symptoms. Conclusions: The creation of an OPEU in a CCC allows getting around the taboo of palliative care. It supports the dialogue between the oncologist and the pt, allows the pt to make the therapeutic project evolve toward a life project, avoiding costly unreasonable obstinacy.
Rescue-free laxation response with methylnaltrexone treatment in cancer patients with opioid-induced constipation: The impact of baseline ECOG status.
Authors: Boniol Scott , Slatkin Neal E. , Stambler Nancy , Israel Robert J. 
Published: June 2021

e24083 Background: Opioid-induced constipation (OIC) is a common side effect of opioid treatment for cancer-related pain. Methylnaltrexone (MNTX) is a peripherally active µ-opioid receptor antagonist indicated for OIC that does not affect opioid central analgesia. We assessed if baseline Eastern Cooperative Oncology Group (ECOG) status impacted the rescue-free laxation (RFL) responses among cancer patients with OIC treated with repeated doses of MNTX. Methods: This pooled post hoc analysis from 2 randomized, placebo-controlled, institutional review board–approved clinical studies included cancer patients with OIC (study 302, NCT00402038; study 4000, NCT00672477). Study 302 compared subcutaneous MNTX 0.15 mg/kg vs placebo and study 4000 compared body weight‒based subcutaneous MNTX 8 mg (38–< 62 kg) or 12 mg (³ 62 kg) vs placebo. The data were stratified by baseline ECOG status (< 2 vs ≥ 2). Endpoints included the number of patients with RFL responses within 4 hours after ≥ 2 of the first 4 doses and the number of patients with RFL response within 4 hours of treatment for patients who received all 7 doses. Results: The intent-to-treat analysis included 43 patients with an ECOG < 2 (placebo = 20; MNTX = 23) and 187 patients with an ECOG ≥ 2 (placebo = 94; MNTX = 93). Those with an ECOG < 2 were younger (mean age 58 vs 65 years), predominantly male (60.5% vs 51.3%), and used a higher daily dose of oral morphine equivalent (190.7 vs 180.0 mg/d) compared with those with an ECOG ≥ 2. Cancer patients with an ECOG < 2 treated with MNTX had a significantly greater RFL response within 4 hours after ≥ 2 of the first 4 doses compared with placebo (56.5% vs 5.0%, P = 0.0003). Similar results were reported for patients with an ECOG ≥ 2 (57.0% vs 5.3%, P < 0.0001). Compared with placebo, the MNTX group had a greater proportion of patients with an RFL response, whether they had at least 1 RFL response or up to 7 RFL responses out of 7 doses, with significant treatment differences with each additional RFL per 7 doses among cancer patients with an ECOG ≥ 2 (Table). Conclusions: RFL response rates in cancer patients were significantly greater in the MNTX group vs the placebo group regardless of baseline ECOG status; responses were similar between the 2 groups despite a higher daily dose of opioids in the group with an ECOG > 2. Clinical trial information: NCT00402038; NCT00672477. [Table: see text]
Development and Evaluation of Deep Learning-based Automated Segmentation of Pituitary Adenoma in Clinical Task
Authors: Wang He , Zhang Wentai , Li Shuo , Fan Yanghua , Feng Ming , Wang Renzhi 
Published: June 2021

Abstract

Context
The resection plan of pituitary adenoma (PA) needs preoperative observation of the sellar region. Radiomics prediction requires high-quality segmentations. Manual delineation is time-consuming and subject to rater variability.

Objective
This work aims to create an automated segmentation method for the sellar region, several tools to extract invasiveness-related features, and evaluate their clinical usefulness by predicting the tumor consistency.

Methods
Patients included were diagnosed with pituitary adenoma at Peking Union Medical College Hospital. A deep convolutional neural network, called gated-shaped U-net (GSU-Net), was created to automatically segment the sellar region into 8 classes. Five magnetic resonance imaging (MRI) features were extracted from the segmentation results, including tumor diameters, volume, optic chiasma height, Knosp grading system, and degree of internal carotid artery contact. The clinical usefulness of the proposed methods was evaluated by the diagnostic accuracy of the tumor consistency.

Results
A total of 163 patients with confirmed pituitary adenoma were included as the first group and were randomly divided into a training data set and test data set (131 and 32 patients, respectively). Fifty patients with confirmed acromegaly were included as the second group. The Dice coefficient of pituitary adenoma in important image slices was 0.940. The proposed methods achieved accuracies of more than 80% for the prediction of 5 invasive-related MRI features. Methods derived from the automatic segmentation showed better performance than original methods and achieved areas under the curve of 0.840 and 0.920 for clinical models and radiomics models, respectively.

Conclusion
The proposed methods could automatically segment the sellar region and extract features with high accuracy. The outstanding performance of the prediction of the tumor consistency indicates the methods’ clinical usefulness for supporting neurosurgeons in judging patients’ conditions, predicting prognosis, and other downstream tasks during the preoperative period.
Women With Polycystic Ovary Syndrome Have an Increased Risk of Major Cardiovascular Events: a Population Study
Authors: Berni Thomas R , Morgan Christopher L , Rees D Aled 
Published: June 2021

Abstract

Context
The effects of polycystic ovary syndrome (PCOS) on cardiovascular morbidity and mortality are unclear.

Objective
This work aims to establish the relative risk of myocardial infarction (MI), stroke, angina, revascularization, and cardiovascular mortality for women with PCOS.

Methods
Data were extracted from the Clinical Practice Research Datalink Aurum database. Patients with PCOS were matched to controls (1:1) by age, body mass index (BMI) category, and primary care practice. The primary outcome was the time to major adverse cardiovascular event (MACE); a composite end point incorporating MI, stroke, angina, revascularization and cardiovascular mortality. Secondary outcomes were the individual MACE end points.

Results
Of 219 034 individuals with a diagnosis of PCOS, 174 660 (79.7%) met the eligibility criteria and were matched. Crude rates of the composite end point, MI, stroke, angina, revascularization, and cardiovascular mortality were respectively 82.7, 22.7, 27.4, 32.8, 10.5, and 6.97 per 100 000 patient-years for cases, and 64.3, 15.9, 25.7, 19.8, 7.13, and 7.75 per 100 000 patient-years for controls. In adjusted Cox proportional hazard models (CPHMs), the hazard ratios (HRs) were 1.26 (95% CI, 1.13-1.41), 1.38 (95% CI, 1.11-1.72), 1.60 (95% CI, 1.32-1.94), and 1.50 (95% CI, 1.08-2.07) for the composite outcome, MI, angina, and revascularization, respectively. In a time-dependent CPHM, weight gain (HR 1.01; 1.00-1.01), prior type 2 diabetes mellitus (T2DM) (HR 2.40; 1.76-3.30), and social deprivation (HR 1.53; 1.11-2.11) increased risk of progression to the composite end point.

Conclusion
The risk of incident MI, angina, and revascularization is increased in young women with PCOS. Weight and T2DM are potentially modifiable risk factors amenable to intervention.
Early Modern Grand Tourer in Poland-Lithuania
Authors: Basista Jakub 
Published: June 2021

Early Modern Grand Tourer in Poland-Lithuania. Fiction or Real Possibility?
In the last fifty or so years, Grand Tour has become a very popular and extensively researched phenomenon. Although mainstream researchers have analyzed various aspects of the Grand Tour, they have tended to adopt a narrow definition limited to the experiences of young English gentlemen undertaking a study tour of Italy and France. This article poses a somewhat provocative question: was the Grand Tour feasible as a study tour of an English gentleman visiting Poland- Lithuania? Based on contemporary travel writing, the author reveals the challenges and the difficult logistics of such an undertaking.