bluuebunny/crossref_metadata_2025 huggingface dataset:
Development of "Online Cancer Patient Assistance Pathway" (OCPAP) technology platform to provide treatment guidance for cancer patients in developing countries.
Authors: Jotwani Amit Kumar , Jain Rashie , Sharma Varun , Goud Rakesh Shankar , Haranath Ravishankar , Koppaka Deepak , Mishra Ashutosh , Komanduri Suneel Kaushik , Chilukuri Ramakrishna Prasad , Sangwan Himanshu
Published: October 2019

11

Background: As per global oncology workforce data published by ASCO in 2018 the new patients per oncologist ratio ranges between 700 to 10,000 in developing countries compared to 70-200 in developed ones. This gross deficit of oncologists adversely affects quality of care resulting in poor outcomes for patients. The onco.com OCPAP technology platform is designed to help patients get free standardised treatment recommendations as per standard protocols. Methods: We identified four basic input points with objective responses that could be entered by the patients/caregivers - cancer type (organ affected), treatment done so far (none, surgery, chemo, radiation), stage of disease and performance status (active, weak and bedridden). Proprietary knowledge database was created by our oncologists as per standard guidelines based on which the platform provides output in terms of specialist to be consulted (medical, radiation, surgical oncologist), recommended treatment (surgery, radiation, chemotherapy, palliation or supportive care), and diagnostic information required. Technically, OCPAP uses an online interface to capture the input from the user regarding the condition of the patient. The user interface then sends the input to our REST API based application running on a server. The server application runs our proprietary recommendation algorithm that is optimised to search our database containing proprietary knowledge graph created by our oncologists. Once a match is found, our algorithm provides the most relevant information that matches the patient’s condition. This information is then provided to the user through the same interface in simple language to help them make right treatment decisions in consultation with their treating doctor. Results: OCPAP platform has benefited 18,000 patients from 14 countries and has helped them better understand their treatment options. Majority of users are from developing countries in Indian subcontinent, Africa and Middle East. Conclusions: The OCPAP platform can help millions of cancer patients with limited access to qualified oncologists get better understanding of their treatment options.
Afatinib as a novel potential treatment option for NRG1 fusion-positive tumors.
Authors: Laskin Janessa J. , Cadranel Jacques , Renouf Daniel John , Weinberg Benjamin A. , Goto Yasushi , Duruisseaux Michaël , Tolba Khaled , Branden Eva , Doebele Robert Charles , Heining Christoph , Schlenk Richard F. , Cheema Parneet Kaur , Jones Martin R. , Trombetta Domenico , Muscarella Lucia A. , Cseh Agnieszka , Solca Flavio , Liu Stephen V.
Published: October 2019

110

Background: Neuregulin 1 (NRG1) is a growth factor that binds HER3/4 and activates ErbB signalling pathways. NRG1 gene fusions function as oncogenic drivers and represent a potential therapeutic target across tumour types. Afatinib, an ErbB-family blocker, is a potential treatment option for some patients with NRG1 fusion-positive ( NRG1+) tumours, as supported by preclinical evidence and clinical case reports. Of 13 patients with NRG1+ lung adenocarcinoma (ADC; n = 9), pancreatic ADC (n = 2), cholangiocarcinoma (n = 1), and ovarian cancer (n = 1) treated with afatinib, eight patients achieved a best response of partial response (PR; median duration 7.3 months, range 3–12), three patients had stable disease (SD) and two patients had progressive disease. Methods: Here, we report the clinico-pathological and molecular characteristics and current status of four additional cases of afatinib-treated NRG1+ tumours. Results: Patient 1, 66 year-old female, never-smoker with metastatic non-mucinous lung ADC. CD74-NRG1 fusion was identified, and 5th-line afatinib initiated. PR is ongoing after 16 months. Patient 2, 43 year-old female, non-smoker with advanced invasive mucinous lung ADC. CD74-NRG1 fusion was identified and 3rd-line afatinib initiated (PR, 18 months); treatment is ongoing following local progression. Patient 3, 69 year-old male, with KRAS-mutated metastatic colorectal cancer. Following a right hemicolectomy and liver/lung metastasectomies, a novel POMK-NRG1 fusion was detected and afatinib initiated (SD, 4 months). Eight months after initiation, afatinib treatment is ongoing, in combination with radiotherapy, with SD. Patient 4, 54 year-old male, with KRAS-wild-type metastatic pancreatic cancer. Following progression on chemotherapy, APP-NRG1 fusion was detected as part of the Personalized Oncogenomics study (NCT02155621), and afatinib initiated; PR is ongoing after 7 months. Conclusions: These findings add to a growing body of evidence that afatinib is a potential treatment option for patients with NRG1+ tumours. Prospective study is ongoing/planned in the Drug Rediscovery Protocol trial (DRUP; NCT02925234) and Targeted Agent and Profiling Utilization Registry study (TAPUR; NCT02693535).
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.
A transcriptomic landscape of cancer and TME in early-stage lungadenocarcinomaby single-cell sequencing.
Authors: Wang Siwei , Zhou Yiqi , Fan Jue , Yin Rong
Published: October 2019

33

Background: Immuno-checkpoint inhibition therapies has been revolutionizing cancer treatment. Yet only a fraction of patients show durable responses , whereas the majority of treated patients show relatively low clinical response. This difference is likely to be caused by the heterogeneity of both cancer cells and cells involved in the tumor microenvironment (TME). However, the extent of this heterogeneity, how it is shaped by other factors in the tumor and vice versa, remains poorly understood. Methods: To explore the heterogeneity of lung adenocarcinoma, we obtained tumor tissuesand peripheral blood froma cohort of 30 treatment-naive patients. For each sample, single-cell RNA sequencingand whole exome sequencing(WES) wereperformed. A graph-based unsupervised clusteringmethod was usedand cell types were assignedto clusters based on marker gene expression. The sub-types of both cancer cells and TME cells along with their gene expression patterns were comparedbetween different cancer stages and mutation status. Results: we presented a landscape of cancer and TME transcriptome in human lung adenocarcinoma at single-cell resolution. We found the expression of cancer cells exhibits distinct characteristics with different TNM stages. For instance, the tumor cells of a patient classified as T1aN2M0 highly express genes enriched in the cell migration pathway. By comparing TME cells among patients with different mutation status, we identified changes in various T cell subtypes and tumor-infiltrating myeloid cells. Conclusions: This study provided a detailed cell atlas of lung adenocarcinoma and identified gene expression patterns that are unique to specific TNM stages. Moreover, single-cell analyses offer valuable knowledgeof immune changes for each patient subgroup, providing ausefultool for the rational design of immunetherapies.
Budget poor, but outcomes rich: How to set up tele-assisted systems in a regional and rural cancer center.
Authors: Poprawski Dagmara Magdalena
Published: October 2019

4

Background: Tyranny of distance in Australia has motivated oncologists to try innovations in oncology care to improve cost efficiency, access, and compliance. This is often done with little budget availability as health funds are metrocentric. The aim is to bring novel approaches to utilisation of oncology care and show its applicability to most countries even with financial constraints. Methods: Mt Gambier Hospital is a regional hospital in South Eastern South Australia (SE SA). The data collected from clinics was commenced in January 2016, to gain knowledge of epidemiology of cancer in the region, and numbers of patients seen. Despite gold standard cancer care being performed in consultations which are face-to-face, we rolled out telemedicine consultations. We also, implemented a Survivorship Care Model, and entered into a Teletrials Project which sets up a regional trials centre with support from a tertiary hospital, Flinders Medical Centre. Results: Telemedicine has been made in Mt Gambier Hospital’s cancer service a part of every day practice to save patients from unnecessary travel. From January 2016, until May 2019, there were 812 consultations with nurse practitioner, 2542 consultations with consultant in clinic, and 246 telemedicine consultations. Survivorship clinic has been implemented according to South Australian Framework for Survivorship with no extra funding. Since 2017, 49 patients were seen with curative therapy. A re-alignment of appointment scheduling will see 6 patients in the next 2 months, thus increasing clinic potential. Teletrials Project was born from collaboration with Flinders Medical Centre, and gained funding by Beat Cancer South Australia. We are now entering into final stages of Governance agreement for our 1st trial, 18 months from commencing the project. Since then, we also got 2 more collaboration grants from Beat Cancer SA. Conclusions: With limited resources, regional cancer centres are able to maximise their patient outcomes by applying novel strategies. These novel ways of doing things, may be able to be implemented on either existing budgets or through collaboration with metropolitan cancer centres to attract financial grants to improve patient outcomes.
Development of a blood-based cancer screening assay with a novel multivariate cancer risk score (MCRS) model by integrating shallow WGS data and plasma protein markers.
Authors: Mao Mao , Li Shiyong , Ren Qingqi , Zhong Guolin , Li Ruizhen , Chen Yan , Jin Xin , Li Jia , Ju Jia , Long Guanghui
Published: October 2019

45

Background: Despite the increase of our knowledge about carcinogenesis and recent successful development of innovative cancer drugs, cancer mortality has only slightly decreased in the past decades. Cancer early detection is probably the most cost-effective means to reduce cancer mortality as prognosis is much better when cancer is detected and treated at the early stage. Recently studies have demonstrated that blood-based mutation detection approaches may be effective to identify asymptomatic cancer patients from general population. Methods: Here we reported a novel multivariate cancer risk score (MCRS) model that interrogates shallow whole genome sequencing (WGS) data from cell-free DNA (cfDNA) and protein markers results in a single blood draw. Results: In a prospective clinical study consisting of 76 stage I-IV cancer patients and 152 normal individuals, the MCRS model demonstrated 60% sensitivity at 98.5% specificity. In order to validate clinical utility of the MCRS model in detection of cancer patients, we collated the data from a previous study of occult maternal malignancies from 1.93 million pregnant women undergoing NIPT test between 2016 and 2017. 466 out of the 639 pregnant women who tested positive for multiple chromosomal aneuploidies (MCAs) in the initial NIPTs (i.e. 0.06 - 0.1x WGS), have also underwent the protein markers test. Out of the 466 subjects, 39 maternal malignant cancer cases were diagnosed with a median follow-up of 399 days (IR, 303 - 487 days) by imaging and histology. The cancer patients presented a wide spectrum of cancer types, the most frequent being breast cancer (10 cases), liver cancer (8) and lymphoma (8), at stage II to IV. This subgroup of 466 subjects was selected as an independent validation cohort for our study. Through our new method, we analyzed shallow WGS and proteins data. The MCRS model allowed 28 of the 39 (71.8%) cancer cases to be identified with a positive predictive value of 73.7% and specificity of 97.7%. Conclusions: Taken together, these data demonstrate the MCRS model holds promise for detecting cancer in asymptomatic individuals, particularly in the populations at high risk of cancer.
Mutation spectrum of major cancer driver genes in Vietnamese NSCLC patients.
Authors: Tran Uyen Vu , Pham Hong-Anh Thi , Tran Thanh-Truong , Dang Anh-Thu Huynh , Le Dinh-Thong Vu , Nguyen Son-Lam Vu , Nguyen Ngoc-Vu Vu , Nguyen Vu Trieu , Vo Binh Thanh , Nguyen Nguyen Huu , Nguyen Chu Van , Pham Cam Phuong , Do Thuy Thanh , Dinh Kiet Truong , Do Han Ngoc , Phan Minh-Duy , Nguyen Hoai-Nghia , Tran Le Son , Giang Hoa
Published: October 2019

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Background: Non-small cell lung cancer (NSCLC) is the most common subtype of lung cancer and leading cause of cancer related death worldwide. Acquired genetic alterations in major driver genes including EGFR, KRAS, NRAS, BRAF, ALK and ROS1 are the most common mutations in NSCLC and certain mutations are associated with drug sensitivity or resistance. Hence, the mutation profiles of NSCLC patients are vital to guide targeted therapy and monitor the tumor recurrence, thereby improving the survival rate. The latest Globocan data showed that lung cancer ranks as the second most common cancer in Vietnam with high incidence and mortality rate. Nonetheless, the mutation spectrum of Vietnamese NSCLC patients has not been profiled thoroughly and current views on mutation testing largely rely on data obtained from previous prospective studies in Caucasian or East Asian cohorts. Methods: Massive parallel sequencing was employed to detect both somatic point mutations and rearrangement in six major driver genes in tissue biopsies from 350 NSCLC patients in Vietnam. The χ2/Fisher’s exact test was performed to compare mutation frequency between different cohorts. Additionally, both univariate and multivariate tests were used to identify clinical factors associated with mutation prevalence. Results: EGFR (32.3%) and KRAS (20%) accounted for the most frequently mutated genes, followed by ALK (5.4%), ROS1 (2.9%), BRAF (1.1%) and NRAS (0.6%). Our data showed a unique pattern of mutation profiles in Vietnamese NSCLC patients, with significant enrichment of KRAS mutation as compared to reported East Asian cohorts (20% versus 8%-10%, p < 0.05). Furthermore, EGFR and KRAS mutation frequencies were significantly associated with patients’ gender, with EGFR mutations more commonly detected in female than in male (48.1% versus 26.9%, p < 0.00001) while higher KRAS mutation frequency in male than in female (30.7% versus 9.2%, p < 0.0001). Young patients aged below the median age of 61 years had significantly higher tendency to acquire rearrangements in ALK (p = 0.02) and ROS1 (p = 0.03) than elderly patients. Conclusions: To our knowledge, our study is the first to reveal the mutation profiles of major druggable genes in a large cohort of Vietnamese NSCLC patients.
CancerScreen: A novel ultrasensitive liquid biopsy for early-stage cancer detection by ctDNA Duplex Sequencing and Tissue of Origin identification with supervised machine learning.
Authors: Ding Elizabeth , Zhao Zhilong , Xue Hongsheng , Li Jianxin , Lei Ting , Ma Xuezhen , Wu Jianlin , Huang Qin
Published: October 2019

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Background: Circulating tumor DNA (ctDNA) in blood holds promise as a cancer-specific biomarker for early-stage cancer diagnosis. However, detection of ultra-low mutation allelic frequency (MAF) of ctDNA at early stages of cancer is infeasible by conventional next generation sequencing (NGS). Using duplex sequencing with unique molecular identifiers (UMIs) and custom-designed probes, we tested the hypothesis that ctDNA duplex sequencing with UMIs was able to detect ultra-low MAF of ctDNA in patients with early-stage cancers. Methods: A 128-gene panel that contains probes targeted to clinical relevant genome variations in cancers of the lung, stomach, and esophagus was designed and validated with reference DNA and controls using ctDNA duplex sequencing with UMIs. A data analysis pipeline was implemented withimproved algorithms for variant calling, blood tumor mutational burden (bTMB) calculation, and supervised machine learning for tissue-of-origin primary cancer identification. Results: We designed and validated a ctDNA duplex sequencing with UMIs assay that enables simultaneous detection of 128 clinical relevant geneswith SNPs, indels, amplifications, and fusions in a single blood test. Compared to conventional ctDNA NGS, our assay achieved high sensitivity (over 82%) and specificity (over 96%) with LOD at 0.1% MAF for stage I lung, gastric and esophageal cancers with the sequencing depth at 30,000x from a cohort of 136 clinical samples. Results also showed significant concordance of MAF and TMB between DNA from tumor tissues and plasma ctDNA. Our deep learning predictive model with novel algorithms and features for tumor tissue-of-origin classification achieved an overall 85% accuracy. Conclusions: In this study, a novel ultrasensitive assay was designed and validated for accurate detection of MAF at 0.1% from plasma ctDNA of multiple tumors, and accurate classification on tissue-of-origin for major primary cancers using supervised deep learning. The results of this liquid biopsy study from initial clinical testing showed its promise on clinical applications for early-stage cancer diagnosis.
New platform for collecting real-world data on directing clinical trial optimization, especially for rare mutations in lung cancer.
Authors: Qiu Weini , Wu Fengying , Yang Yan , Dong Jie , Wei Xiaoqi , Xie Xingyi , Duan Meiling , Li Yapin , Ou Sai-Hong Ignatius
Published: October 2019

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Background: In China, lung cancer pts see different hospitals in various places, but medical info is not shared among different medical centers. It is difficult to obtain complete medical info to evaluate the quality of drug treatment & prognosis of lung cancer pts. Methods: We created a pt’s self-submitted data interactive platform to record and store pt’s info such as locations, gender, diagnosis, treatment etc., & to follow up on pt’s real-world medical info in real time. Based these records, a scientific method was used to establish a real medical treatment data set for lung cancer pts to reflect actual medical treatment process. Results: Between 9/13/2018 - 5/30/2019, 5 rare mutation projects (ROS1, RET, EGFR exon20, HER2, EGFR resistance) were initiated. Data cutoff is 6/15/2019. In all 5 projects, we collected by far the largest number of real-world pt’s self-submitted data reported in China. All cases were confirmed by commercial NGS or PCR. In all 5 projects, there were significant differences in regional distributions of patients. The median age for all 5 projects are: 50, 55, 57, 56 and 55, respectively. A total of 95.6% of pts submitted their 1st-line treatment info & 93.8% received 1st-line treatment. Conclusions: Pts self-submitted interactive platform provides valuable insights for trial design to reconsider site selection, & pts’ criteria selection for the success of the trial in rare mutations lung cancer. [Table: see text]
Prognostic significance of cyclin B1 expression plus clinicopathologic features in hormonal positive, HER2 negative early breast cancer in King Chulalongkorn Memorial Hospital During 2010-2015.
Authors: Takonkitsakul Kanchanaporn , Thanakit Voranuch , Poovorawan Nattaya , Uttamapinan Suleepon , Sriuranpong Virote , Parinyanitikul Napa
Published: October 2019

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Background: Approximately one third of hormonal receptor (HR) positive, HER2 negative early breast cancer reported disease relapse after adjuvant treatments. Both clinicopathologic features and multigene assays consider to be predicting factor of relapse. Cyclin B1, one of proliferative markers used in OncotypeDx has been explored previously for predicting recurrence in this subgroup of breast cancers. Our study aims to determine the prognostic significance of cyclin B1 in combination with clinicopathologic factors in recurrent HR positive, HER2 negative breast cancer. Methods: Two-hundred and forty-five HR positive, HER2 negative early breast cancers who were diagnosed during 2010 to 2015 in King Chulalongkorn Memorial Hospital were retrospectively reviewed. All clinicopathologic factors and level of cyclin B1 expression were evaluated. Correlation of cyclin B1 expression with clinicopathologic features was also compared in recurrence and non-recurrence group. Results: In 245 patients, 65 patients were recurrence group while 180 patients were non-recurrence group. Mean age at breast cancer diagnosis were 53 years. Recurrence group had high pathological staging, tumor grade, LVI, Ki-67 and lymph node involvement compared to non-recurrence group ( p < 0.05). Mean cyclin B1 expression was 9.61% (19.62 % in recurrence group and 5.88 % in non-recurrence group; p< 0.001). We have used cut-off of cyclin B1 expression at ≥ 10 % (7th decile) to classify high and low of expression. Cyclin B1 high expression were demonstrated in 53.4% of recurrence group compared to 22.4% of non-recurrence group. In multivariate analysis, tumor grade (OR 8.42, 95%CI 1.04-67.98; p = 0.046), receiving neoadjuvant chemotherapy (NAC) (OR 4.27, 95%CI 1.41-12.87; p = 0.010) and % cyclin B1 expression (OR 1.04, 95%CI 1.00-1.07; p = 0.013) were associated with recurrent disease. Five-year relapse free survival for cyclin B1 low and high expression were 84.9% and 60.1%, respectively. Conclusions: Tumor grade, receiving NAC and % cyclin B1 expression were associated with risk of recurrence in HR positive and HER2 negative early breast cancer.
Not preoperative but prechemotherapy lymphocyte count predicts outcome of non-small cell lung cancer patients treated with adjuvant chemotherapy.
Authors: Lee Hyun Woo , Kang Seok Yun , Han Jae Ho , Yoo Byoung Moo
Published: October 2019

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Background: Several systemic inflammatory markers in blood have been suggested as prognostic factors in various cancers. We investigated the prognostic significance of neutrophil-to-lymphocyte ratio (NLR) and absolute lymphocyte count (ALC) in patients (pts) with non-small cell lung cancer (NSCLC) treated with adjuvant chemotherapy. Methods: A retrospective review was conducted on 108 pts who received adjuvant chemotherapy after surgical resection of NSCLC. Disease-free survival (DFS) and overall survival (OS) of pts with high NLR and ALC ( > median value) before surgery or chemotherapy were compared to those of pts with low NLR and ALC (≤median value). Results: The number of pts at AJCC stage IB, IIA, IIB, IIIA, and IIIB were 1, 38, 9, 58, and 2, respectively. Adenocarcinoma,squamous cell carcinoma, and other histologic types were present in 66 (61.1%), 32 (29.6%), and 10 (9.3%) patients, respectively. The most frequently used chemotherapy regimen was vinorelbine/cisplatin (81 pts), followed by paclitaxel/carboplatin (22 pts), and others (5 pts). A total of 61 (56.5%) pts received adjuvant radiotherapy (before adjuvant chemotherapy: 53 pts). Preoperative NLR and ALC were not associated with clinicopathologic characteristics including stage and histologic types. High prechemotherapy NLR and low ALC were more frequently observed in pts who underwent radiotherapy before chemotherapy (p < 0.0001). The median follow-up duration was 61 (29-153) months for survivors. The longer median DFS was observed in pts with stage IB or II (65 vs. 22 months, p = 0.025) and high prechemotherapyALC (65 vs. 20 months, p = 0.036), without significant difference in OS. On the other hand, NLR and preoperative ALC were not associated with outcome of pts. Conclusions: The present study suggests that high prechemotherapyALC is associated with favorable outcome in stage IB-III NSCLC pts who received adjuvant chemotherapy after surgical resection.
Magnetic resonance-guided high intensity focused ultrasound (MR-HIFU) hyperthermia for primary rectal cancer: A virtual feasibility analysis.
Authors: Perry Kaitlyn , Staruch Robert , Pichardo Samuel , Huang Yuexi , McGuffin Merrylee , Partanen Ari , Wong Shun , Czarnota Gregory J. , Hynynen Kullervo , Chan Kelvin K. , Chu William
Published: October 2019

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Background: MR-HIFU Hyperthermia (HT) is a non-invasive treatment modality with real-time thermometry that ensures accurate and precise heating of a target with minimal effect on adjacent tissue. This energy deposition within a tumour can produce local bioeffects resulting in thermal chemo- and radiosensitization. MR-HIFU has been shown to be safe and feasible in a companion phase I study for recurrent rectal cancer. The purpose of this study is to determine the feasibility of MR-HIFU in treating primary rectal tumours. Methods: With ethics approval, the anatomic characteristics and surrounding structures of rectal tumours diagnosed at Sunnybrook from 2014-2019 were retrospectively analyzed. Three orthogonal views of MR images were used to determine the potential ultrasound (US) beam path and organs at risk (OAR). In part 2 of the study, the gross tumour volume was delineated for 30 rectal tumours (10 low, mid &high). Image datasets were imported into the Sonalleve MR-HIFU workstation for virtual treatment simulation and planning to determine tumour targetability, coverage, optimal patient set-up, and transducer positioning. Results: Of the 105 tumours analyzed, 36, 52, and 17 were low, mid, and high, respectively. The average width of the acoustic window (sciatic notch) for the US beam path was 5.8 ± 1.4cm, average tumour length was 5.24 ± 2.0cm, and average beam path (skin to tumour edge) was 7.3 ± 1.9cm. Eighty one percent of tumours were ≤ 0.3cm from an OAR. Of the 24 virtually simulated tumours to date, 6/8 lower, 6/8 mid, and 1/8 upper rectal tumours were targetable by MR-HIFU. Conclusions: This is the first virtual analysis to evaluate MR-HIFU HT targetability in primary rectal cancer. Results from this study will support MR-HIFU HT as an option to enhance the treatment of primary rectal cancer. Acknowledgments: This study has been funded by the Canadian Cancer Society. Patient & tumour characteristics. [Table: see text]