[18]F-fluoroethyl-l-tyrosine positron emission tomography for radiotherapy target delineation: Results from a Radiation Oncology credentialing program.

Background and purpose: The [18]F-fluoroethyl-l-tyrosine (FET) PET in Glioblastoma (FIG) study is an Australian prospective, multi-centre trial evaluating FET PET for newly diagnosed glioblastoma management. The Radiation Oncology credentialing program aimed to assess the feasibility in Radiation Oncologist (RO) derivation of standard-of-care target volumes (TVMR) and hybrid target volumes (TVMR+FET) incorporating pre-defined FET PET biological tumour volumes (BTVs). Materials and methods: Central review and analysis of TVMR and TVMR+FET was undertaken across three benchmarking cases. BTVs were pre-defined by a sole nuclear medicine expert. Intraclass correlation coefficient (ICC) confidence intervals (CIs) evaluated volume agreement. RO contour spatial and boundary agreement were evaluated (Dice similarity coefficient [DSC], Jaccard index [JAC], overlap volume [OV], Hausdorff distance [HD] and mean absolute surface distance [MASD]). Dose plan generation (one case per site) was assessed. Results: Data from 19 ROs across 10 trial sites (54 initial submissions, 8 resubmissions requested, 4 conditional passes) was assessed with an initial pass rate of 77.8 %; all resubmissions passed. TVMR+FET were significantly larger than TVMR (p < 0.001) for all cases. RO gross tumour volume (GTV) agreement was moderate-to-excellent for GTVMR (ICC = 0.910; 95 % CI, 0.708-0.997) and good-to-excellent for GTVMR+FET (ICC = 0.965; 95 % CI, 0.871-0.999). GTVMR+FET showed greater spatial overlap and boundary agreement compared to GTVMR. For the clinical target volume (CTV), CTVMR+FET showed lower average boundary agreement versus CTVMR (MASD: 1.73 mm vs. 1.61 mm, p = 0.042). All sites passed the planning exercise. Conclusions: The credentialing program demonstrated feasibility in successful credentialing of 19 ROs across 10 sites, increasing national expertise in TVMR+FET delineation.

A proposed framework for the implementation of head and neck cancer treatment at a new cancer center from a radiation oncology perspective.

BACKGROUND: Establishing a new head and neck cancer (HNC) treatment center requires multidisciplinary team management and expertise. To our knowledge, there are no clear recommendations or guidelines in the literature for the commencement of HNC radiation therapy (RT) at a new cancer center. We propose a novel framework outlining the necessary components required to set-up a new radiation therapy HNC treatment. METHODS: We reviewed the infrastructure and methodology in the commencement of HNC radiation therapy in our cancer care center and invited several external, experienced metropolitan head and neck radiation oncologists to develop a novel consensus guideline that may be used by new RT centers to treat HNC. Recommendations were presented to our internal and external staff specialists using a survey questionnaire with ratings utilized to determine consensus using pre-defined thresholds as per the American Society of Clinical Oncology Guidelines Methodology Manual. CONCLUSION: This consensus recommendation aims to improve RT utilization whilst advocating for optimal patient outcomes by presenting a framework for new radiation therapy centers ready to step up and manage the treatment of head and neck cancer patients. We propose these evidence-based consensus guidelines endorsed by external HNC radiation oncologists.

Nutrition outcomes and treatment toxicities in patients with head and neck cancer receiving helical intensity-modulated radiotherapy.

BACKGROUND: Helical intensity-modulated radiotherapy (H-IMRT) provides excellent limitation of dose to tissues not requiring treatment, although acute toxicity still occurs. The present study aimed to determine how treatment-related acute toxicities affect nutrition outcomes in patients with head and neck cancer. METHODS: A prospective observational study was conducted in 194 patients undergoing curative intent H-IMRT with or without other treatment modalities. Weight outcomes (kg) and acute toxicity and dysphagia data were collected during treatment using Common Toxicity Criteria for Adverse Effects (CTCAE), version 4.0. RESULTS: Significant weight loss (> 10%) was observed in 30% of high nutritional risk patients and 7% of low nutritional risk patients. Nausea, adjusted for baseline dysphagia, in high nutritional risk patients and nausea, dysphagia and pharyngeal mucositis in low nutritional risk patients were significant factors in explaining the percentage loss in baseline weight to treatment completion. CONCLUSIONS: Significant weight loss remains an issue during treatment, despite improvements in radiotherapy technology and high-level multidisciplinary care.

Diagnostic criteria for Buerger's disease: International Consensus of VAS - European Independent Foundation in Angiology/Vascular Medicine.

Buerger's disease (BD) remains a debilitating condition and early diagnosis is paramount for its effective management. Despite many published diagnostic criteria for BD, selective criteria have been utilized in different vascular centers to manage patients with BD worldwide. A recent international Delphi Consensus Study on the diagnostic criteria of BD showed that none of these published diagnostic criteria have been universally accepted as a gold standard. Apart from the presence of smoking, these published diagnostic criteria have distinct differences between them, rendering the direct comparison of patient outcomes difficult. Hence, the expert committees from the Working Group of the VAS-European Independent Foundation in Angiology/Vascular Medicine critically reviewed the findings from the Delphi study and provided practical recommendations on the diagnostic criteria for BD, facilitating its universal use. We recommend that the 'definitive' diagnosis of BD must require the presence of three features (history of smoking, typical angiographic features and typical histopathological features) and the use of a combination of major and minor criteria for the 'suspected' diagnosis of BD. The major criterion is the history of active tobacco smoking. The five minor criteria are disease onset at age less than 45 years, ischemic involvement of the lower limbs, ischemic involvement of one or both of the upper limbs, thrombophlebitis migrans and red-blue shade of purple discoloration on edematous toes or fingers. We recommend that a 'suspected' diagnosis of BD is confirmed in the presence of a major criterion plus four or more minor criteria. In the absence of the major criterion or in cases of fewer than four minor criteria, imaging and laboratory data could facilitate the diagnosis. Validation studies on the use of these major and minor criteria are underway.

Intracranial ependymoma in an adult patient with multiple primary malignancies.

The incidence of multiple primary malignancies (MPM) is increasing, and therefore, it has become highly important for clinicians to consider the concept of MPM when treating oncology patients. In this case report, we follow the clinical course of a patient diagnosed with a new intracranial lesion, an ependymoma, on a background of MPM. We explore the barriers implicating the delay in her diagnosis, dissect the challenges in managing her disease and emphasise the importance of social determinants in optimising her care.

Proteome profiling of salivary small extracellular vesicles in glioblastoma patients.

BACKGROUND: Extracellular vesicles (EVs) play a critical role in intercellular communication under physiological and pathological conditions, including cancer. EVs cargo reflects their cell of origin, suggesting their utility as biomarkers. EVs are detected in several biofluids, and their ability to cross the blood-brain barrier has highlighted their potential as prognostic and diagnostic biomarkers in gliomas, including glioblastoma (GBM). Studies have demonstrated the potential clinical utility of plasma-derived EVs in glioma. However, little is known about the clinical utility of saliva-derived EVs in GBM. METHODS: Small EVs were isolated from whole mouth saliva of GBM patients pre- and postoperatively. Isolation was performed using differential centrifugation and/or ultracentrifugation. EVs were characterized by concentration, size, morphology, and EVs cell-surface protein markers. Protein cargo in EVs was profiled using mass spectrometry. RESULTS: There were no statistically significant differences in size and concentration of EVs derived from pre- and post GBM patients' saliva samples. A higher number of proteins were detected in preoperative samples compared to postoperative samples. The authors found four highly abundant proteins (aldolase A, 14-3-3 protein ε, enoyl CoA hydratase 1, and transmembrane protease serine 11B) in preoperative saliva samples from GBM patients with poor outcomes. Functional enrichment analysis of pre- and postoperative saliva samples showed significant enrichment of several pathways, including those related to the immune system, cell cycle and programmed cell death. CONCLUSIONS: This study, for the first time, demonstrates the feasibility of isolating and characterizing small EVs from pre- and postoperative saliva samples from GBM patients. Preliminary findings encourage further large cohort validation studies on salivary small EVs to evaluate prognosis in GBM.

A pilot study: Metabolic profiling of plasma and saliva samples from newly diagnosed glioblastoma patients.

BACKGROUND: Despite aggressive treatment, more than 90% of glioblastoma (GBM) patients experience recurrences. GBM response to therapy is currently assessed by imaging techniques and tissue biopsy. However, difficulties with these methods may cause misinterpretation of treatment outcomes. Currently, no validated therapy response biomarkers are available for monitoring GBM progression. Metabolomics holds potential as a complementary tool to improve the interpretation of therapy responses to help in clinical interventions for GBM patients. METHODS: Saliva and blood from GBM patients were collected pre and postoperatively. Patients were stratified conforming their progression-free survival (PFS) into favourable or unfavourable clinical outcomes (>9 months or PFS ≤ 9 months, respectively). Analysis of saliva (whole-mouth and oral rinse) and plasma samples was conducted utilising LC-QqQ-MS and LC-QTOF-MS to determine the metabolomic and lipidomic profiles. The data were investigated using univariate and multivariate statistical analyses and graphical LASSO-based graphic network analyses. RESULTS: Altogether, 151 metabolites and 197 lipids were detected within all saliva and plasma samples. Among the patients with unfavourable outcomes, metabolites such as cyclic-AMP, 3-hydroxy-kynurenine, dihydroorotate, UDP and cis-aconitate were elevated, compared to patients with favourable outcomes during pre-and post-surgery. These metabolites showed to impact the pentose phosphate and Warburg effect pathways. The lipid profile of patients who experienced unfavourable outcomes revealed a higher heterogeneity in the abundance of lipids and fewer associations between markers in contrast to the favourable outcome group. CONCLUSION: Our findings indicate that changes in salivary and plasma metabolites in GBM patients can potentially be employed as less invasive prognostic biomarkers/biomarker panel but validation with larger cohorts is required.

Enteral nutrition support and treatment toxicities in patients with head and neck cancer receiving definitive or adjuvant helical intensity-modulated radiotherapy with concurrent chemotherapy.

BACKGROUND: Enteral nutrition (EN) is often required in patients with head and neck cancer (HNSCC); however, initiation criteria is limited or inconsistent. This study aimed to describe the relationship of treatment toxicities and requirement for EN and investigate toxicity and baseline characteristics association with EN duration. METHODS: Acute toxicities and baseline characteristics were collected from patients with HNSCC (n = 110) undergoing H-IMRT. Percentage EN contributing to estimated requirements and EN duration were measured. RESULTS: The threshold for patients needing ≥50% of estimated requirements via EN increased from week 3 to 4 for grade ≥2 oral/pharyngeal mucositis, dysgeusia, thick saliva and nausea, and for grade 3 dysphagia. Patients with grade 2-3 dysphagia had a reduced risk of ceasing EN compared to those with grade 0-1 dysphagia. CONCLUSIONS: Using acute toxicities in clinical practice may be a useful tool to inform prompt initiation of EN prior to decline in nutritional status and anticipate EN duration.

Development of a customisable 3D-printed intra-oral stent for head-and-neck radiotherapy.

Intra-oral stents (including mouth-pieces and bite blocks) can be used to displace adjacent non-involved oral tissue and reduce radiation side effects from radiotherapy treatments for head-and-neck cancer. In this study, a modular and customisable 3D printed intra-oral stent was designed, fabricated and evaluated, to utilise the advantages of the 3D printing process without the interruption of clinical workflow associated with printing time. The stent design used a central mouth-opening and tongue-depressing main piece, with optional cheek displacement pieces in three different sizes, plus an anchor point for moulding silicone to fit individual patients' teeth. A magnetic resonance imaging (MRI) study of one healthy participant demonstrated the tissue displacement effects of the stent, while providing a best-case indication of its comfort.

An International Delphi Consensus on Diagnostic Criteria for Buerger's Disease.

BACKGROUND: Buerger's disease (BD) remains a debilitating condition. Despite multiple published diagnostic criteria for BD, none is universally accepted as a gold standard. METHODS: We conducted a 2-round modified Delphi consensus study to establish a consensus on the diagnostic. The questionnaire included statements from several commonly used diagnostic criteria for BD. Qualitative and quantitative analysis methods were performed. An agreement level of 70% was applied. RESULTS: Twenty nine experts from 18 countries participated in this study. Overall, 75 statements were circulated in Round 1. Of these, 28% of statements were accepted. Following comments, 21 statements were recirculated in Round 2 and 90% were accepted. Although more than 90% of the experts did not agree that the diagnosis of BD can be based only on clinical manifestation, none of the nonclinical manifestations of BD were agreed as a part of the diagnostic criteria. There was an agreement that a history of tobacco consumption in any form, not necessarily confined to the current use, should be a part of the diagnostic criteria of BD. The history of thrombophlebitis migrans, even if not present at presentation, was accepted as a clue for BD diagnosis. It was also agreed that discoloration of the toes or fingers could be included in the diagnostic criteria of BD. Experts agreed that histology results could differentiate BD from atherosclerosis obliterans and other types of vasculitis. The presence of corkscrew collaterals on imaging and burning pain reached the agreement at the first round but not at the second. There was no consensus regarding age cut-off, the requirement of normal lipid profile, and normal blood glucose for BD diagnosis. CONCLUSIONS: The present study demonstrated discrepancies in the various published diagnostic criteria for BD and their selective utilization in routine clinical practice worldwide. We propose that all published diagnostic criteria for BD be re-evaluated for harmonization and universal use.

A qualitative analysis of the barriers and enablers faced by Australian rural general practitioners in the non-pharmacological management of congestive heart failure in community dwelling patients.

BACKGROUND: Congestive heart failure (CHF) is a significant health problem in Australia, and disproportionately affects rural Australians. Management of CHF in Australia is heavily centred around the general practitioner (GP). Australian and international literature indicates there is a gap between current and best practice in CHF management. There is little known about the non-pharmacological aspects of management, or CHF management in a rural Australian context. This study aimed to identify what Australian GPs practicing in the Northern Rivers Region of New South Wales, Australia, perceived were the barriers and enablers in the non-pharmacological management of CHF amongst community dwelling patients, to inform healthcare access, resourcing and delivery in Australian rural environments. METHODS: Qualitative study involving a realist thematic analysis of data collected from semi-structured face-to-face interviews. RESULTS: Fifteen GPs and GP trainees participated. Four interlinked key themes underpinning GPs' experiences with non-pharmacological management of CHF were interpreted from the interview data: (1) resources, (2) complexity of heart failure, (3) relationships, and (4) patient demographics, priorities and views affect how patients engage with non-pharmacological management of CHF. CONCLUSION: Rural Australian GPs face considerable barriers to non-pharmacological management of CHF. The data suggests that increased rural Australian health services and community transportation, multidisciplinary management, and stronger professional networks have the potential to be invaluable enablers of CHF management. Further research exploring non-pharmacological management of CHF in other rural contexts may provide additional insights to better inform rural healthcare access and resourcing.

Milestones in thromboangiitis obliterans: a position paper of the VAS-European independent foundation in angiology/vascular medicine.

Even today thromboangiitis obliterans has disease features that remain misunderstood or underappreciated. The epidemiology, etiology and pathophysiology of the disease are still unclear. Biomarkers and disease activity markers are lacking, thus clinical assessment is difficult. We are still struggling to establish unique diagnostic, staging and treatment criteria. This is an academic-collaborative effort to describe the pathophysiology, the clinical manifestations, the diagnostic approach, and the challenges of management of patients with TAO. A systematic search for relevant studies dating from 1900 to the end of 2020 was performed on the PubMed, SCOPUS, and Science Direct databases. Given the intriguing nature of presentation of TAO, its management, to some extent is not only different in different regions of the world but also varies within the same region. Following this project, we discovered ambiguity, overlap and lack of clear-cut criteria for management of TAO. An international group of experts however came to one conclusion. They all agree that management of TAO needs a call for action for a renewed global look with multi-center studies, to update the geographical distribution of the disease and to establish a unique set of diagnostic criteria and a consensus-based guideline for best treatment based on current evidence.

Isolation of Circulating Tumour Cells in Patients With Glioblastoma Using Spiral Microfluidic Technology - A Pilot Study.

Glioblastoma (GBM) is the most common and aggressive type of tumour arising from the central nervous system. GBM remains an incurable disease despite advancement in therapies, with overall survival of approximately 15 months. Recent literature has highlighted that GBM releases tumoural content which crosses the blood-brain barrier (BBB) and is detected in patients' blood, such as circulating tumour cells (CTCs). CTCs carry tumour information and have shown promise as prognostic and predictive biomarkers in different cancer types. Currently, there is limited data for the clinical utility of CTCs in GBM. Here, we report the use of spiral microfluidic technology to isolate CTCs from whole blood of newly diagnosed GBM patients before and after surgery, followed by characterization for GFAP, cell-surface vimentin protein expression and EGFR amplification. CTCs were found in 13 out of 20 patients (9/20 before surgery and 11/19 after surgery). Patients with CTC counts equal to 0 after surgery had a significantly longer recurrence-free survival (p=0.0370). This is the first investigation using the spiral microfluidics technology for the enrichment of CTCs from GBM patients and these results support the use of this technology to better understand the clinical value of CTCs in the management of GBM in future studies.

Dosimetric evaluation of a patient-specific 3D-printed oral positioning stent for head-and-neck radiotherapy.

As head-and-neck radiotherapy treatments become more complex and sophisticated, and the need to control and stabilise the positioning of intra-oral anatomy becomes more important, leading the increasing use of oral positioning stents during head-and-neck radiotherapy simulation and delivery. As an alternative to the established practice of creating oral positioning stents using wax, this study investigated the use of a 3D printing technique. An Ender 5 3D printer (Creality 3D, Shenzhen, China) was used, with PLA+ "food-safe" polylactic acid filament (3D Fillies, Dandenong South, Australia), to produce a low-density 3D printed duplicate of a conventional wax stent. The physical and dosimetric effects of the two stents were evaluated using radiochromic film in a solid head phantom that was modified to include flexible parts. The Varian Eclipse treatment planning system (Varian Medical Systems, Palo Alto, USA) was used to calculate the dose from two different head-and-neck treatment plans for the phantom with each of the two stents. Examination of the resulting four dose distributions showed that both stents effectively pushed sensitive oral tissues away from the treatment targets, even though most of the phantom was solid. Film measurements confirmed the accuracy of the dose calculations from the treatment planning system, despite the steep density gradients in the treated volume, and demonstrated that the 3D print could be a suitable replacement for the wax stent. This study demonstrated a useful method for dosimetrically testing novel oral positioning stents. We recommend the development of flexible phantoms for future studies.

A prospective study investigating the efficacy and toxicity of definitive ChemoRadiation and ImmunOtherapy (CRIO) in locally and/or regionally advanced unresectable cutaneous squamous cell carcinoma.

BACKGROUND: Patients with unresectable advanced cutaneous squamous cell carcinoma (cSCC) are generally treated with palliative intent. Immune checkpoint blockade has significant activity in the palliative setting in patients with recurrent or metastatic cSCC. This single arm phase 2 prospective study aims to investigate the combination of curative intent chemoradiation and durvalumab (anti-PD-L1 checkpoint inhibitor) for this patient cohort. METHODS: Patients with unresectable locally and or regionally advanced pathologically confirmed cSCC (stage III-IVa) deemed fit for CRIO by consensus of the Multidisciplinary meeting will be eligible. In the first stage of a two-stage minimax design, we aim to recruit a total of 15 patients. If fewer than 7 patients achieved a complete response in the first stage, we will conclude the treatment is not more effective than standard treatment. The co-primary endpoints of CRIO are the safety of treatment (acute and late toxicities) and the rate of complete response. Secondary endpoints would include overall survival, progression free survival, and locoregional control. Translational research endpoints including biomarkers (CD73, CD39, PD-1, PD-L1) will also be explored utilising multiplex immunohistochemistry on tumour biopsy samples obtained prior to commencing treatment and during treatment (week 2). In addition, the utility of CXCR-4 PET/CT scan will be explored. DISCUSSION: CRIO is a novel trial evaluating the combination of curative intent chemoradiotherapy with concurrent and adjuvant durvalumab for patients with unresectable stage III-IVa cSCC. TRIAL REGISTRATION: Trial registered with the Australian New Zealand Clinical Trial Registry (ACTRN12618001573246).

Survival outcomes following modern multidisciplinary management of oral squamous cell carcinoma in Australia.

OBJECTIVE: Oral squamous cell carcinoma (SCC) has been traditionally described as a highly lethal disease. This study aims to provide updated multi-institutional data on the survival of patients with oral SCC in Australia. STUDY DESIGN: Retrospective survival analysis was performed between 2008 and 2016. All new patients with oral SCC treated with curative intent were recruited from 2 high-volume Australian head and neck oncology centers. Outcomes were measured in overall survival (OS), disease-specific survival (DSS), disease-free survival, and salvage rates for recurrences. RESULTS: Survival analysis included 771 patients with oral SCC. Five-year OS and DSS were 66.1% and 79.7%, respectively. Stage I and II oral SCC had significantly better survival than higher stages. Five-year OS and DSS for patients with stage I SCC were 79.7% and 93.4%, respectively, and for patients with stage IVB they were 37.9% and 54.3%, respectively. Two hundred forty-nine patients had disease recurrence (32.3%), with 66 patients (26.5% remaining disease free post salvage treatment. CONCLUSION: Survival outcomes for oral SCC among Australian patients have improved, possibly due to advances in multidisciplinary care. Early detection of oral SCC leads to highly favorable prognosis; there is therefore an opportunity for routine oral cancer screening to be performed by community health practitioners with the aim of improving survival from oral SCC.

Impact of radiopacified bone cement on radiotherapy dose calculation.

BACKGROUND AND PURPOSE: Radiopacifiers are introduced to bone cements to provide the appearance of bone in kilovoltage (kV) radiographic images. For higher energy megavoltage (MV) radiotherapy treatment beams, however, these radiopacifiers do not cause a bone-like perturbation of dose. This study therefore aimed to determine the impact of the barium-contrasted plastic-based cement materials on radiotherapy dose calculations. MATERIALS AND METHODS: The radiological properties of a physical sample of bone cement were characterised by computed tomography (CT) imaging and transmission measurements. Monte Carlo simulations of percentage depth-dose profiles were performed to determine the possible dose error for MV treatment beams. Dose differences were then investigated for clinical volumetric modulated radiotherapy treatment plans, with and without density overrides applied. RESULTS: Differences of up to 7% were observed at the downstream interface of a 0.6 cm thick bone cement layer, compared to bone. Differences in planning target volume dose-volume metrics varied between -0.5% and 2.0%. CONCLUSION: Before planning radiotherapy treatments for patients who have undergone cranioplasty, every effort should be made to identify whether a radiopacified bone cement has been implanted. Density overrides should be applied to minimise dose calculation errors, whenever bone cement is used.

Peak systolic velocity ratio derived from quantitative vessel analysis for restenosis after femoropopliteal intervention: a multidisciplinary review from Endovascular Asia.

With technological improvements in the endovascular armamentarium, there have been tremendous advances in catheter-based femoropopliteal artery intervention during the last decade. However, standardization of the methodology for assessing outcomes has been underappreciated, and unvalidated peak systolic velocity ratios (PSVRs) of 2.0, 2.4, and 2.5 on duplex ultrasonography have been arbitrarily but routinely used for assessing restenosis. Quantitative vessel analysis (QVA) is a widely accepted method to identify restenosis in a broad spectrum of cardiovascular interventions, and PSVR needs to be validated by QVA. This multidisciplinary review is intended to disseminate the importance of QVA and a validated PSVR based on QVA for binary restenosis in contemporary femoropopliteal intervention.

Circulating biomarkers in patients with glioblastoma.

Gliomas are the most common tumours of the central nervous system and the most aggressive form is glioblastoma (GBM). Despite advances in treatment, patient survival remains low. GBM diagnosis typically relies on imaging techniques and postoperative pathological diagnosis; however, both procedures have their inherent limitations. Imaging modalities cannot differentiate tumour progression from treatment-related changes that mimic progression, known as pseudoprogression, which might lead to misinterpretation of therapy response and delay clinical interventions. In addition to imaging limitations, tissue biopsies are invasive and most of the time cannot be performed over the course of treatment to evaluate 'real-time' tumour dynamics. In an attempt to address these limitations, liquid biopsies have been proposed in the field. Blood sampling is a minimally invasive procedure for a patient to endure and could provide tumoural information to guide therapy. Tumours shed tumoural content, such as circulating tumour cells, cell-free nucleic acids, proteins and extracellular vesicles, into the circulation, and these biomarkers are reported to cross the blood-brain barrier. The use of liquid biopsies is emerging in the field of GBM. In this review, we aim to summarise the current literature on circulating biomarkers, namely circulating tumour cells, circulating tumour DNA and extracellular vesicles as potential non-invasively sampled biomarkers to manage the treatment of patients with GBM.

HNF4α pathway mapping identifies wild-type IDH1 as a targetable metabolic node in gastric cancer.

OBJECTIVE: Gastric cancer (GC) is a leading cause of cancer mortality. Previous studies have shown that hepatocyte nuclear factor-4α (HNF4α) is specifically overexpressed in GC and functionally required for GC development. In this study, we investigated, on a genome-wide scale, target genes of HNF4α and oncogenic pathways driven by HNF4α and HNF4α target genes. DESIGN: We performed HNF4α chromatin immunoprecipitation followed by sequencing across multiple GC cell lines, integrating HNF4α occupancy data with (epi)genomic and transcriptome data of primary GCs to define HNF4α target genes of in vitro and in vivo relevance. To investigate mechanistic roles of HNF4α and HNF4α targets, we performed cancer metabolic measurements, drug treatments and functional assays including murine xenograft experiments. RESULTS: Gene expression analysis across 19 tumour types revealed HNF4α to be specifically upregulated in GCs. Unbiased pathway analysis revealed organic acid metabolism as the top HNF4α-regulated pathway, orthogonally supported by metabolomic analysis. Isocitrate dehydrogenase 1 (IDH1) emerged as a convergent HNF4α direct target gene regulating GC metabolism. We show that wild-type IDH1 is essential for GC cell survival, and that certain GC cells can be targeted by IDH1 inhibitors. CONCLUSIONS: Our results highlight a role for HNF4α in sustaining GC oncogenic metabolism, through the regulation of IDH1. Drugs targeting wild-type IDH1 may thus have clinical utility in GCs exhibiting HNF4α overexpression, expanding the role of IDH1 in cancer beyond IDH1/2 mutated malignancies.