bluuebunny/crossref_metadata_2025_split huggingface dataset:
Intraoperative radiotherapy (IORT) for surgically resected brain metastases: Local control and dosimetric analysis.
Authors: Cifarelli Christopher Paul , Vargo John Austin , Hack Joshua , Renz Paul B. , Poplawski Linda , Jacobson Geraldine M. , Kahl Klaus Henning , Brehmer Stefanie , Sarria Gustavo , Giordano Frank Anton 
Published: October 2019

114 Background: The optimal use of adjuvant radiation following surgical resection of large brain metastases (BM) remains undetermined. Time to initiation following surgery and target delineation both impact local control (LC). Intraoperative radiotherapy (IORT) allows for elimination of lag time between surgery and radiation, direct cavity targeting, and safe dose escalation beyond traditional stereotactic radiosurgery (SRS). The current study provides an analysis of local disease control and dosimetric parameters related to intracranial IORT. Methods: Retrospective data was collected on patients treated with IORT immediately following surgical resection of BMs at three institutions according to the approval of individual IRBs. All patients were treated with the Zeiss Intrabeam device (Carl Zeiss Meditech, Germany) using spherical applicators ranging from 1.5 to 4.0cm with 50kV output. Statistical analyses were performed using SPSS (IBM) with endpoints of LC and incidence of RN, with p < 0.05 considered significant. Dosimetric comparisons between IORT and SRS were made based on V10, V12, and dose homogeneity based on percent of GTV receiving greater than 20Gy or 30Gy. Results: 54 patients were treated with IORT with a median age of 64 years. The most common primary diagnosis was non-small cell lung cancer (40%) with the most common location in the frontal lobe (38%). Median follow-up was 7.2 months and 1-year LC rate was 88% with radiation necrosis (RN) present in 4 patients (7%). The dosimetric comparison of a single IORT case revealed non-target V10 and V12 volumes as 24.75cm3 and 14.76cm3, respectively, for the SRS treatment plan of 16Gy to the margin. The V10 and V12 for the IORT treatment plan were 20.83cm3 and 9.93cm3 with a surface dose of 30Gy. The volumes exceeding 20Gy and 30Gy in the SRS plan were 14.73cm3 and 0.328cm3, respectively, while the corresponding volumes in the IORT plan were 9.8cm3 and 0cm3. Conclusions: IORT is a safe and effective means of delivering adjuvant radiation to the BM resection cavities with a high rate of LC, low incidence of RN, increased homogeneity of target dose and ability to escalate dose beyond traditional SRS plans.
Pharmacologic studies of CDH17/CD3 bispecific antibodies to treat colorectal and pancreatic cancers.
Authors: Wong Kwong-Fai , Tai William Chi-shing , Chow Kronos , Luk John M. , Staunton Don 
Published: October 2019

116 Background: Immunotherapy has emerged as a new hope for cancer patients who do not respond to conventional therapies. In addition to the widely investigated immune checkpoint inhibitors such as PD-L1 antibody, bispecific T cell redirecting antibodies have also drawn much attention from pharmaceutical companies. The popularity of bispecific T cell engager has been increasing since the US FDA’s accelerated approval of blinatumomab for treatment of haematological malignancies. The clinical efficacy of such engagers in solid tumors have however remained to be demonstrated. Cadherin-17 (CDH17) is a promising immunotherapeutic target for gastrointestinal (GI) cancers. It is a highly tumor-specific antigen with restricted expression limited to the tight junction of intestine that is normally inaccessible to biologics. CDH17 overexpression correlates with tumor burden and poor prognosis. Methods: Fully humanized CDH17/CD3 bispecific antibodies were generated. T cell-mediated cytotoxicity was tested in vitro and in vivo. Safety was addressed in cynomolgus monkeys with intestinal CDH17 level equivalent to that of human. Results: One lead antibody, ARB202 exhibited high-affinity binding to CDH17 and CD3. In the presence of CDH17-positive pancreatic cancer cells, ARB202 stimulated in vitro IL-2 release in CD3/CD28-expanded PBMC. In the absence of tumor cells ARB202 stimulated cytokine production in PBMCs required over 600-fold greater concentrations. ARB202 specifically directed in vitro T cell killing of GI cancer cells expressing CDH17, but not of cells lacking CDH17 expression. In mouse xenograft models reconstituted with human immune cells, ARB202 demonstrated significant tumor growth inhibition with concomitant IL-2 response. No dose-dependent toxicities on cynomolgus monkeys were observed over a 3-log dose range. ARB202 displayed favourable in vivo pharmacokinetic profiles in mice and monkeys. ARB202 is a stable bispecific antibody retaining functional activity after incubation for a month at 37°C at pH6.0. Conclusions: ARB202 is a promising candidate for clinical trials. A proprietary cell line is generated for the pilot manufacturing of ARB202 for IND enabling studies.
BP-C1 in treatment of pretreated metastatic breast cancer: A meta-analysis of two randomized, double-blind and placebo-controlled multicenter studies.
Authors: Larsen Stig Einride , Butthongkomvong Kritiya , Manikhas Alexey , Fagertun Hans Erik 
Published: October 2019

12 Background: To compare the effect of BP-C1 versus equal looking placebo in heavily pre-treated metastatic breast cancer (MBC) patients and to evaluate the efficacy of BP-C1 according to number of negative receptors. Methods: The study sample consisted of 61 patients from two randomized, double blinded and placebo controlled multicentre studies with semi-cross-over design. By randomization, 31 patients were allocated to BP-C1 and 30 to equal looking placebo treatment for 32 days. Twenty-five of the 30 patient allocated to placebo were switched to BP-C1 after finalizing the placebo period. A joint sample of 56 patients received one daily intramuscular injection of 0.07 ml/kg BW of BP-C1 for at least one cycle of 32 days. Receptor status including Estrogen, Progesterone and Human epidermal growth factor receptor was analysed prior to entering the study and available in 54 of the 56 patients. CT scans were performed at screening and after every 32-days of treatment, and were blindly analysed by one independent radiologist. The sum of target lesion diameters (SLD), RECIST classification and disease control rate (DCR) defined as patients obtaining at least stabile disease (SD) at the end of treatment was the main variables. Results: The SLD increased non-significantly by 1.5mm (5.7%) in the BP-C1 group and significantly (p < 0.001) by 13.6 mm (26.2%) in the placebo group during the 32 days of treatment. The difference between groups with respect to SLD and DCR was significant in favour of BP-C1 (p < 0.001). The tumour growth in the joint BP-C1 group was 2.5mm (5.9%) and DCR was 89.1% [95% CI: 38.1 – 96.0]. Nine of the 56 patients reported 26 Adverse Events (AE) related to BP-C1; all of mild to moderate degree. SLD increased 16.2% (p = 0.03) in patients with three positive receptors, 7.5% (p = 0.02) in the group with one negative receptor, 2.5% in the group of two negative receptors and 0.8% in triple negative patients. The tumor growth declined with increasing number of negative receptors (r = -0.26; p = 0.05). Conclusions: BP-C1 treatment of pre-treated MBC patients controlled the cancer growth with few mainly mild AE’s. The BP-C1 efficacy increased with the number of negative receptors. Clinical trial information: NCT03603197. Clinical trial information: NCT02783794.
Characteristics and treatment response of chronic lymphocytic leukemia patients in Dharmais National Cancer Centre Hospital, Indonesia.
Authors: Sutandyo Noorwati , Siregar Nia Novianti , Tadjoedin Hilman , Syafei Syafrizal , Agustina Julyanti 
Published: October 2019

121 Background: Chronic lymphocytic leukemia (CLL) was a common hematological malignancy in America and Europe, but rarely found in Asia. Differences in clinical characteristics and treatment response were suspected. This study aimed to find out characteristics and treatment response of patient with CLL in Dharmais National Cancer Centre Hospital Indonesia. Methods: This was a retrospective cohort study of CLL patients in Dharmais Hospital during 2013-2015. Data were retrieved from medical record included patients’ demography, blood examination, bone marrow puncture, and immunophenotyping. Prognosis factors such as Rai and Binet staging system were studied. Results: A total of 36 CLL patients were retrieved. Most of patients (58.3%) were male. Median age was 58.5 years old. As much as 25.9% of patients were asymptomatic. There were 17 patients (47.2%) with negative CD5, and most of them (63.2%) had isolated splenomegaly (p = 0.019). Twenty patients (55.6%) were high-risk based on Rai staging group, but there were only 14 patients (38.9%) were high-risk based on Binet staging group. Positive CD13 was found in 30.6% patients and classified as high risk Rai (p < 0.001) and Binet (p = 0.043) staging group. Treatment response was available in 12 cases, consisted of 8 (66.7%) partial responses, 3 (25.0%) progressive diseases, and 1 (8.3%) stable disease. Conclusions: Chronic lymphocytic leukemia is a rare disease in Indonesia. Patients tend to be younger and have worse prognosis. Many cases are categorized as high-risk and present without specific clinical symptoms. Early detection is challenging in the future for better management of CLL cases.
The association between neutrophil-to-lymphocyte ratio and treatment response in nasopharyngeal cancer patients of Cipto Mangunkusumo General Hospital in 2015-2018: A retrospective cohort study.
Authors: Cahyanur Rahmat , Irawan Cosphiadi , Rahmawati Sari , Nasman Nadia 
Published: October 2019

123 Background: Nasopharyngeal Cancer (NPC) is the most common head and neck cancer in Indonesia and mostly diagnosed at advanced stage. The patients with same stage of the disease have shown variety of responses against first line chemotherapy, suggesting other factors that could play a role in determining the treatment outcome. Meanwhile, neutrophil-to-lymphocyte ratio (NLR) has been studied to be a prognostic factor in many malignancies. Objective: This study aimed to determine the association between NLR and treatment response in advanced-stage NPC patients of Cipto Mangunkusumo General Hospital (RSCM) in 2015-2018. Methods: We evaluated the medical record of 45 advanced-stage NPC patients that visited RSCM in 2015-2018 retrospectively. The NLR was calculated using the neutrophil and lymphocyte count prior the first chemotherapy. We categorized NLR ≥ 4 as high. We categorized the treatment response by response (CR and PR) and non-response (SD and PD). Results: There were 45 patients included in this study. Demographic profile of the patients were dominated by male (80,0%) with mean age 45.58 (±14.5) years old. The mean of NLR was 7.396 (±5.182). We found 32 (71.1%) patients had high NLR (cut off > 4). Majority of patients with high NLR (71.9%) did not respond to first line treatment. The association between NLR and treatment response was statistically significant ( p = 0.048). Conclusions: We found that high NLR values are associated with poor treatment response in NPC patients. Keywords: Nasopharyngeal cancer, neutrophil-to-lymphocyte ratio, treatment response.
Preservation of long-term neurocognitive function by hippocampal avoidance whole-brain radiotherapy in patients with brain metastases.
Authors: Wang Buhai , Fu Shiwei , Huang Yuxiang 
Published: October 2019

124 Background: To investigate the preservation of long-term neurocognitive function in patients after hippocampal avoidance whole-brain radiotherapy (HA-WBRT). Methods: For the retrospective analysis, 50 patients diagnosed with brain metastases were selected and divided into two groups from 2015-01-01 to 2017-12-31 at the Department of Oncology, Jiangsu Subei People's Hospital. Group A (n=27) was hippocampal avoidance whole-brain radiotherapy group; group B (n=23) was whole brain radiation therapy (WBRT) group. Neurocognitive function was statistically analyzed at 3, 6, 9, 12, and 24 months after radiotherapy, as scored by the MMSE (Mine-Mental State Examination) scales and the MoCA (Montreal Cognitive Assessment) scales. The OS, PFS and tumor recurrence sites of the two groups was also analyzed. Results: After 12, 24 months after radiotherapy, there was a significant difference between the two groups. The cognitive function of the hippocampal protection group was significantly higher than that of the non-hippocampal protection group (P<0.05). There was no significant difference in OS (P=0.2) and PFS (P=0.18) between the two groups. 14 patents in group A and 12 patents in group B had brain tumor recurrence after radiation, only one patient in group A occurred 5 mm within the edge of the hippocampus (P>0.05). Conclusions: First, HA-WBRT has a protective effect on long-term neurocognitive function. Second, there was no statistically significant different on OS and PFS in patients who underwent HA-WBRT or WBRT. Third, HA-WBRT didn’t increase the risk of brain tumor recurrence within the edge of the hippocampus.
Establish a predictive model for high-risk de novo metastatic prostate cancer patients by machine learning.
Authors: SU Po-Jung , Fang Yu-Ann , Chang Yung-Chun , Kuo Yung-Chia , Lin Yung-Chang 
Published: October 2019

13 Background: For de novo metastatic prostate cancer (mPC)) patients, their prognosis may be really different. Some of these patients response very well to hormone therapy with durable survival, but others may be not. For those poor prognosis patients, if we could predict them as high risk patients when diagnosed, and provide aggressive upfront chemotherapy or novel hormonal therapy, they might get better treatment outcomes. Methods: We used data of prostate cancer patients from 2000 to 2016 in Chang Gung Research Database. There are 799 de novo mPC patients with castration. We predicted the possibility for these patients progressed to metastatic castration-resistant prostate cancer (mCRPC) in 1 year and find the high risk group patients. Then we figured out the best features for prediction from the best classifier with Recursive Feature Elimination. Results: The de nove mPC patients who pregressed to mCRPC in 1 year, whose mOS is 21.9 months is worse than who progressed to mCRPC beyond 1 year significantly, whose mOS is 80.7 months. (adjusted hazard ratio[aHR]: 6.43, P<0.001). The overall performance of machine learning by XGBoost is the best in all predictive models for high risk patients. (AUC=0.7000, Accuracy=0.7143). We excluded the features with missing data over 50%, then put all other features in the model. (AUC=0.7042, Accuracy=0.7239). But we got the best performance with only 11 features, including age, time from diagnosis to castration, nadir PSA, hemoglobin, eosinophil/white blood cell ratio, alkaline phosphatase, alanine transaminase, blood urea nitrogen, creatinine, prothrombin time, and secondary primary cancer, by Recursive Feature Elimination. (AUC=0.7131, Accuracy=0.7267). Conclusions: We found the predictive model has better predictive accuracy and shorter manuscript time with less features selected by Recursive Feature Elimination.We can predict high risk group in de novo mPC patients and make better clinical decision for treatment with this XGBoost model.
Analysis of local control rate and toxicity of radiotherapy dose of cervical cancer.
Authors: Zhang Hanyi , Lu Shun , Sun Chang , Lang Jin Yi 
Published: October 2019

136 Background: The standard of care for treatment of advanced cervical cancer is the combination of external beam radiation therapy (EBRT) and intracavitary brachytherapy with cisplatin based concurrent chemotherapy. Radiotherapy plays a crucial role in treatment of cervical cancer. Recent GEC-ESTRO guidelines recommend that the dose to 90% (D90) of the high-risk clinical target volume (HRCTV) in cervical cancer be at least 85Gy with higher doses for poor response to radiotherapy. This study was aim to analyze our institution’s patients with locally advanced cervical cancer in regards to whether higher brachytherapy dose delivery lead to a better outcome, and to investigate the proper dose to balance the local control rate and toxicity. Methods: A total of 262 patients with local advanced cervical cancer treated at a single institution were retrospectively analyzed for the association between dosimetry and outcomes. Youden index was used to identify the optimal cut-off point of continuous tumor parameters and divide patients into subgroups. Significance of radiotherapy dose parameters on OS, PFS, LRFS and DMFS and toxicity was evaluated. Results: In the univariate analysis, for both HR-CTV and LR-CTV, the high dose group (EQD2 D90 >75Gy, LR-CTV>68Gy, respectively) have a better LRFS than low-dose groups (P<0.05). LR-CTV remains significance after adjusted for age and FIGO stage. Moreover, in the high-dose LR-CTV group, there is no association between dose of LR-CTV and LRFS was found, however, higher dose of HR-CTV significant associated with higher ratio of side effect was found. In addition, no association of dose of HR-CTV or LR-CTV and OS were found for all patients. Conclusions: Our results showed that dose of LR-CTV may be a useful prognostic factor of LRFS of patients with cervical cancer. Moreover, after D90 of LR-CTV reaches 68Gy, increasing dose did not show a better LRFS but lead to higher ratio of toxicity, supporting that LR-CTV at 68Gy might be a safety and efficacy dose of radiotherapy to the patients with cervical cancer. However, further improved in dose had no significant benefit on local control rate, and it might increase the risks of toxicity.
Exosome-transmitted lncRNA PCGEM1 as a "scaffold" for invasion and metastasis in gastric cancer.
Authors: Zhang Jun 
Published: October 2019

18 Background: It is a major challenge that the hypoxia microenvironment can induce gastric cancer (GC).Understanding the underlying mechanisms and developing effective strategies against GC invasive and metastasis are highly desired in the clinic. Methods: GC cells were cultured under 1% O2 (HGC) and 20% O2 condition (NGC). NGC were co-cultured with HGC- medium. Exosomes from GC were extracted by ultracentrifugation. Electron microscopy images, western-blot and NanoSight particletracking used to analysis the size distributions and number of exosomes. Exosomal long noncoding RNA (lncRNA) profiling was performed using a lncRNA array. The “R” was used to recognize the differentially expressed lncRNAs (DELs). RNA-pulldown and mass spectrometry analysis were recruited to investigate the binding protein of target lncRNA. Results: Compared to NGC, HGC was more capable of invasion and metastasis which was evaluated by scrape and transwell. And HGC-medium induced NGC dissociation. Differential analysis revealed that lncRNA PCGEM1 was specifically expressed in HGC exosomes. PCGEM1 was up-regulated in GC cell and tissue. And the luciferase report confirmed HIF-1α, as a transcription factor, can bind to the promoter sequence of PCGEM1, promotes the overexpression of PCGEM1 in GC. Dii tracer proved that HGC-derived exosomes could be absorbed by NGC. RNA pull-down assay and mass spectrometry analysis showed that SNAI1 and USP9X with PCGEM1 directly. Conclusions: Our results suggest that the overexpressed of HIF-1α can up-regulated the expression of lncRNA PCGEM1 under hypoxia condition. And part of the overexpression PCGEM1 can be encapsulated into exosomes. These exosomes promoted invasion and metastasis of other GC cells. The mechanism was that PCGEM1 can bind both USP9X and SNAI1 at the same time, and under the effect of deubiquitination enzyme USP9X, the expression of SNAI1 increased, thus promoting EMT and thereby promoted the invasion and metastasis of GC cells.
A multidisciplinary-tailored digital solution to data capture in early phase clinical trials.
Authors: Graham Donna M. , Wickert Gemma , Goodwin Leanna , Clarke Joanna , Timmins Carla , Chang Dilshad , Walker Alison , Rees Amanda , Stringer Steffan , Theis Adam , Carter Louise , Cook Natalie , Krebs Matthew , Thistlethwaite Fiona C. , Bradford Jennifer , Royle Jennifer , Hughes Andrew M. 
Published: October 2019

2 Background: Data capture in early phase cancer clinical trials (EPCCT) is usually via paper records with manual transcription to the sponsor’s case report form. Capturing real time trial data directly to computer (eSource) may reduce errors and increase completeness and timeliness of data entry. A simulated system pilot took place between Oct 2018 and Jan 2019 at an EPCCT facility to appraise Foundry Health’s eSource system “ClinSpark”. Aims were to assess consistency and effectiveness of creating electronic templates for source data capture and live data collection compliance. Methods: A multidisciplinary focus group (MFG) (2 research nurses, 1 doctor, 3 data managers) was created to collaborate with Foundry Health staff. Specialised features of the eSource system were adapted to handle the complex needs of EPCCT. The pilot incorporated a 5 day boot camp for familiarisation to the digital platform; a conference room test using simulated patient data; construction of a trial template including contingency planning; and a clinic floor test with live simulated patient data collection using digital tablets. The MFG agreed on a 52 item user acceptance test listing ideal features for a data collection tool, with items classified as high, medium or low priority. Results: During the 3 month pilot, templates for 2 EPCCT were planned and created by the MFG. Using eSource, 43 items (83%) of the acceptance test were passed compared with 27 items (52%) for the current (paper) system. For the 30 high-priority items, eSource passed 30 (100%) compared with 22 for the paper system (73%). The paper system was not superior to eSource for any items assessed. Time saving and potential error reduction were noted as additional benefits. Conclusions: This process demonstrates that a multidisciplinary approach can be used to successfully integrate a customised eSource system working with previously untrained staff. Improved performance across pre-specified domains and potential additional benefits were noted. As FDA encourages use of digital solutions in clinical trials, using eSource provides a potential solution for compliant and efficient data capture from protocol assessments at investigator sites and rapid data transfer to sponsors.