Oral Healthcare Utilization Factors Shaping the Perceived Oral Health Outcome Among Gond Tribes of Chhattisgarh: A Cross-Sectional Study Based on Andersen's Behavioral Model.

INTRODUCTION: The Gonds are a highly ancient and expansive tribal community, ranking among the largest in the world. A review of the literature has suggested that they are more vulnerable to oral diseases and are less inclined to utilize oral health services due to the comprehensive approach that considers the socioeconomic, cultural, and structural factors affecting the Gond community's access to oral health services. Tribal health requires action in the health sector. Utilization is an essential marker of the health status of any population and is necessary to bridge the gap between tribes and the wider portion of the community. Hence, this study was conducted among the Gond tribes of Chhattisgarh to evaluate the oral healthcare utilization factors shaping the perceived oral health outcome using Andersen's behavior model. MATERIALS AND METHODS: This cross-sectional study was carried out among 400 Gond tribes residing in villages of Chhattisgarh. Data was collected through a standardized questionnaire, adapted from Andersen's behavioral model of healthcare utilization during house-to-house survey. The questionnaire included predisposing, enabling, perceived, and evaluated need factors. Oral health status for evaluated need was assessed using the World Health Organization (WHO) Oral Health Assessment form (1997), and the perceived oral health outcome was measured using Oral Health Impact Profile-14 (OHIP-14). Results were computed using descriptive statistics, chi-square test, and one-way analysis of variance (ANOVA). Multivariate analysis was done using binomial logistic regression. RESULTS: The dental visit in the past one year was only 14%. The findings of logistic regression revealed that the perceived oral health outcome was significantly associated with age, occupation, and positive belief in the efficacy of dentist, perceived need, and presence of dental caries. CONCLUSION: The findings of the present study support Andersen's behavioral model and suggest that there is an interrelationship of predisposing characters, predisposing health beliefs, and enabling need factors that determine the likelihood of use of services, which in turn determines the good or bad oral health outcome.

Safety and preliminary efficacy of pembrolizumab following trans-arterial chemoembolization for hepatocellular carcinoma: the PETAL phase Ib study.

BACKGROUND: TACE may prime adaptive immunity and enhance immunotherapy efficacy. PETAL evaluated safety, preliminary activity of TACE plus pembrolizumab and explored mechanisms of efficacy. METHODS: Patients with liver-confined HCC were planned to receive up to 2 rounds of TACE followed by pembrolizumab 200 mg every 21 days commencing 30-days post-TACE until disease progression or unacceptable toxicity for up to 1 year. Primary endpoint was safety, 21-days dose-limiting toxicities (DLT) from pembrolizumab initiation. Secondary endpoints included progression-free survival (PFS) and evaluation of tumour and host determinants of response. RESULTS: Fifteen patients were included in the safety and efficacy population: 73% had non-viral cirrhosis, median age was 72 years. Child-Pugh (CP) class was A in 14 patients. Median tumour size was 4 cm. Ten patients (67%) received pembrolizumab after 1 TACE, 5 patients after 2 (33%). Pembrolizumab yielded no synergistic toxicity nor DLTs post-TACE. Treatment-related adverse events occurred in 93% of patients most commonly skin rash (40%), fatigue and diarrhoea (27%). After a median follow-up of 38.5 months, objective response rate (ORR) 12 weeks post-TACE was 53%. PFS rate at 12 weeks was 93% and median PFS was 8.95 months (95%CI 7.30-NA). Median duration of response was 7.3 months (95%CI: 6.3-8.3). Median OS was 33.5 months (95%CI: 11.6-NA). Dynamic changes in peripheral T-cell subsets, circulating tumour DNA, serum metabolites and in stool bacterial profiles highlight potential mechanisms of action of multi-modal therapy. CONCLUSIONS: TACE plus pembrolizumab was tolerable with no evidence of synergistic toxicity, encouraging further clinical development of immunotherapy alongside TACE.

Somatostatin Receptor Imaging with [18F]FET-ßAG-TOCA PET/CT and [68Ga]Ga-DOTA-Peptide PET/CT in Patients with Neuroendocrine Tumors: A Prospective, Phase 2 Comparative Study.

There is a clinical need for 18F-labeled somatostatin analogs for the imaging of neuroendocrine tumors (NET), given the limitations of using [68Ga]Ga-DOTA-peptides, particularly with regard to widespread accessibility. We have shown that [18F]fluoroethyl-triazole-[Tyr3]-octreotate ([18F]FET-ßAG-TOCA) has favorable dosimetry and biodistribution. As a step toward clinical implementation, we conducted a prospective, noninferiority study of [18F]FET-ßAG-TOCA PET/CT compared with [68Ga]Ga-DOTA- peptide PET/CT in patients with NET. Methods: Forty-five patients with histologically confirmed NET, grades 1 and 2, underwent PET/CT imaging with both [18F]FET-ßAG-TOCA and [68Ga]Ga-peptide performed within a 6-mo window (median, 77 d; range, 6-180 d). Whole-body PET/CT was conducted 50 min after injection of 165 MBq of [18F]FET-ßAG-TOCA. Tracer uptake was evaluated by comparing SUVmax and tumor-to-background ratios at both lesion and regional levels by 2 unblinded, experienced readers. A randomized, blinded reading of both scans was also then undertaken by 3 experienced readers, and consensus was assessed at a regional level. The ability of both tracers to visualize liver metastases was also assessed. Results: A total of 285 lesions were detected on both imaging modalities. An additional 13 tumor deposits were seen in 8 patients on [18F]FET-ßAG-TOCA PET/CT, and [68Ga]Ga-DOTA-peptide PET/CT detected an additional 7 lesions in 5 patients. Excellent correlation in SUVmax was observed between both tracers (r = 0.91; P < 0.001). No difference was observed between median SUVmax across regions, except in the liver, where the median tumor-to-background ratio of [18F]FET-ßAG-TOCA was significantly lower than that of [68Ga]Ga-DOTA-peptide (2.5 ± 1.9 vs. 3.5 ± 2.3; P < 0.001). Conclusion: [18F]FET-ßAG-TOCA was not inferior to [68Ga]Ga-DOTA-peptide in visualizing NET and may be considered in routine clinical practice given the longer half-life and availability of the cyclotron-produced fluorine radioisotope.

Study protocol of LANTana: a phase Ib study to investigate epigenetic modification of somatostatin receptor-2 with ASTX727 to improve therapeutic outcome with [177Lu]Lu-DOTA-TATE in patients with metastatic neuroendocrine tumours, UK.

INTRODUCTION: Suitability for peptide receptor radionuclide therapy (PRRT) for neuroendocrine neoplasia (NENs) depends on presence of somatostatin receptor-2 (SSTR2) determined by [68Ga]Ga-DOTA-peptide-positron emission tomography (PET). Some patients have low or no uptake on [68Ga]Ga-DOTA-peptide-PET, precluding PRRT. The upstream promoter region of SSRT2 is methylated, with percentage of methylation correlating with SSTR2 expression. Demethylating agents increase uptake on PET imaging in vivo such that tumours previously negative on PET become positive, correlating with a dose dependent increase in tumorous SSTR2 expression. LANTana will determine whether treatment with the demethylating agent, ASTX727, results in re-expression of SSTR2 using [68Ga]Ga-DOTA-peptide-PET to image epigenetic modification of the SSTR2 locus, allowing subsequent PRRT. METHODS AND ANALYSIS: 27 participants with a histological diagnosis of NEN (Ki67<55%) with no or low uptake on baseline [68Ga]Ga-DOTA-TATE-PET/CT will be recruited. Patients will receive 5 days of ASTX727 (fixed dose 35 mg decitabine+100 mg cedazuridine). [68Ga]Ga-DOTA-peptide-PET/CT will be repeated day 8±2; where there is significant uptake greater than liver in most lesions, PRRT will be administered. Primary objective is to determine re-expression of SSTR2 on PET imaging. Tolerability, progression-free survival, overall response and quality of life will be assessed. Methylation in peripheral blood mononuclear cells and tumorous methylation will be evaluated. ETHICS AND DISSEMINATION: LANTana has ethical approval from Leeds West Research Ethics Committee (REC Reference: 21/YH/0247).Sponsored by Imperial College London and funded by Advanced Accelerator Applications pharmaceuticals. Results will be presented at conferences and submitted to peer-reviewed journals for publication and will be available on ClinicalTrials.gov. TRIAL REGISTRATION NUMBERS: EUDRACT number: 2020-003800-15, NCT05178693.

Impact of COVID-19 on 1-Year Survival Outcomes in Hepatocellular Carcinoma: A Multicenter Cohort Study.

INTRODUCTION: The COVID-19 pandemic has caused severe disruption of healthcare services worldwide and interrupted patients' access to essential services. During the first lockdown, many healthcare services were shut to all but emergencies. In this study, we aimed to determine the immediate and long-term indirect impact of COVID-19 health services utilisation on hepatocellular cancer (HCC) outcomes. METHODS: A prospective cohort study was conducted from 1 March 2020 until 30 June 2020, correlating to the first wave of the COVID-19 pandemic. Patients were enrolled from tertiary hospitals in the UK and Germany with dedicated HCC management services. All patients with current or past HCC who were discussed at a multidisciplinary meeting (MDM) were identified. Any delay to treatment (DTT) and the effect on survival at one year were reported. RESULTS: The median time to receipt of therapy following MDM discussion was 49 days. Patients with Barcelona Clinic Liver Cancer (BCLC) stages-A/B disease were more likely to experience DTT. Significant delays across all treatments for HCC were observed, but delay was most marked for those undergoing curative therapies. Even though severe delays were observed in curative HCC treatments, this did not translate into reduced survival in patients. CONCLUSION: Interruption of routine healthcare services because of the COVID-19 pandemic caused severe delays in HCC treatment. However, DTT did not translate to reduced survival. Longer follow is important given the delay in therapy in those receiving curative therapy.

NET-02: a randomised, non-comparative, phase II trial of nal-IRI/5-FU or docetaxel as second-line therapy in patients with progressive poorly differentiated extra-pulmonary neuroendocrine carcinoma.

Background: The prognosis for patients with poorly-differentiated extra-pulmonary neuroendocrine carcinoma (PD-EP-NEC) is poor. A recognised first-line (1L) treatment for advanced disease is etoposide/platinum-based chemotherapy with no standard second-line (2L) treatment. Methods: Patients with histologically-confirmed PD-EP-NEC (Ki-67 > 20%; Grade 3) received IV liposomal irinotecan (nal-IRI) (70 mg/m2 free base)/5-FU (2400 mg/m2)/folinic acid, Q14 days (ARM A), or IV docetaxel (75 mg/m2), Q21 days (ARM B), as 2L therapy. Primary endpoint was 6-month progression-free survival (PFS) rate (80% power to demonstrate one-sided 95% lower confidence interval excluded 15% (target level of efficacy: 30%)). Secondary endpoints: objective response rate (ORR), median PFS, overall survival (OS), toxicity and patient-reported quality-of-life (QoL) (ClinicalTrials.gov: NCT03837977). Findings: Of 58 patients (29 each arm); 57% male, 90% ECOG PS 0/1, 10% PS 2, 89.7% Ki-67 ≥ 55%, primary site: 70.7%-gastrointestinal, 18.9%-other, 10.3%-unknown, 91.4%/6.9%/1.7% were resistant/sensitive/intolerant to 1L platinum-based treatment, respectively. The primary end-point of 6-month PFS rate was met by ARM A: 29.6% (lower 95% Confidence-Limit (CL) 15.7), but not by ARM B: 13.8% (lower 95%CL:4.9). ORR, median PFS and OS were 11.1% (95%CI:2.4-29.2) and 10.3% (95%CI:2.2-27.4%); 3 months (95%CI:2-6) and 2 months (95%CI:2-2); and 6 months (95%CI:3-10) and 6 months (95%CI:3-9) in ARMS A and B, respectively. Adverse events ≥ grade 3 occurred in 51.7% and 55.2% (1 and 6 discontinuations due to toxicity in ARMS A and B), respectively. QoL was maintained in ARM A, but not ARM B. Interpretation: nal-IRI/5-FU/folinic acid, but not docetaxel, met the primary endpoint, with manageable toxicity and maintained QoL, with no difference in OS. ORR and median PFS were similar in both arms. This study provides prospective efficacy, toxicity and QoL data in the 2L setting in a disease group of unmet need, and represents some of the strongest evidence available to recommend systemic treatment to these patients. Funding: Servier.

Impact of body mass index in patients receiving atezolizumab plus bevacizumab for hepatocellular carcinoma.

BACKGROUND: Atezolizumab plus bevacizumab (Atezo/Bev) is first line-treatment for unresectable hepatocellular carcinoma (HCC). Body mass index (BMI) has demonstrated predictive value for response to immunotherapy in non-HCC cancer types. Our study investigated the effect of BMI on safety and efficacy of real-life use of Atezo/Bev for unresectable HCC. METHODS: 191 consecutive patients from seven centres receiving Atezo/Bev were included in the retrospective study. Overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and disease control rate (DCR) defined by RECIST v1.1 were measured in overweight (BMI ≥ 25) and non-overweight (BMI < 25) patients. Treatment-related adverse events (trAEs) were evaluated. RESULTS: Patients in the overweight cohort (n = 94) had higher rates of non-alcoholic fatty liver disease (NAFLD) and lower rates of Hepatitis B compared to non-overweight cohort (n = 97). Baseline Child-Pugh class and Barcelona Clinic Liver Cancer stage were similar between cohorts, with lower rates of extrahepatic spread in the overweight group. Overweight patients had similar OS compared to non-overweight (median OS 15.1 vs. 14.9 months; p = 0.99). BMI did not influence median PFS (7.1 vs. 6.1 months; p = 0.42), ORR (27.2% vs. 22.0%; p = 0.44) and DCR (74.1% vs. 71.9%; p = 0.46). There were higher rates of atezolizumab-related fatigue (22.3% vs. 10.3%; p = 0.02) and bevacizumab-related thrombosis (8.5% vs. 2.1%; p = 0.045) in the overweight patients, but overall trAEs and treatment discontinuation were comparable between cohorts. CONCLUSION: Atezo/Bev has comparable efficacy in overweight HCC patients, with an increase in treatment-related fatigue and thrombosis. Combination therapy is safe and efficacious to use in overweight patients, including those with underlying NAFLD.

Applying Lipidomics to Non-Alcoholic Fatty Liver Disease: A Clinical Perspective.

The prevalence of Non-alcoholic fatty liver disease (NAFLD) and associated complications, such as hepatocellular carcinoma (HCC), is growing worldwide, due to the epidemics of metabolic risk factors, such as obesity and type II diabetes. Among other factors, an aberrant lipid metabolism represents a crucial step in the pathogenesis of NAFLD and the development of HCC in this population. In this review, we summarize the evidence supporting the application of translational lipidomics in NAFLD patients and NAFLD associated HCC in clinical practice.

PETAL protocol: a phase Ib study of pembrolizumab after transarterial chemoembolization in hepatocellular carcinoma.

Transarterial chemoembolization (TACE) is the treatment of choice for intermediate-stage hepatocellular carcinoma (HCC). Recent data suggest that TACE may boost the efficacy of anti-PD-1 immunotherapy. The authors present the trial protocol for PETAL, a phase Ib study, which will assess the safety and bioactivity of pembrolizumab, an anti-PD-1 antibody, following TACE in HCC. After a run-in phase evaluating six patients to establish preliminary safety, up to 26 additional participants will be enrolled. Pembrolizumab will be administered three-times weekly for 1 year or until progression, starting 30-45 days after TACE. The primary objective is to determine safety and the secondary objective is to preliminarily evaluate efficacy. Radiological responses will be evaluated every four cycles. Clinical Trial Registration: NCT03397654 (ClinicalTrials.gov).

Discriminatory Changes in Circulating Metabolites as a Predictor of Hepatocellular Cancer in Patients with Metabolic (Dysfunction) Associated Fatty Liver Disease.

Introduction: The burden of metabolic (dysfunction) associated fatty liver disease (MAFLD) is rising mirrored by an increase in hepatocellular cancer (HCC). MAFLD and its sequelae are characterized by perturbations in lipid handling, inflammation, and mitochondrial damage. The profile of circulating lipid and small molecule metabolites with the development of HCC is poorly characterized in MAFLD and could be used in future studies as a biomarker for HCC. Methods: We assessed the profile of 273 lipid and small molecule metabolites by ultra-performance liquid chromatography coupled to high-resolution mass spectrometry in serum from patients with MAFLD (n = 113) and MAFLD-associated HCC (n = 144) from six different centers. Regression models were used to identify a predictive model of HCC. Results: Twenty lipid species and one metabolite, reflecting changes in mitochondrial function and sphingolipid metabolism, were associated with the presence of cancer on a background of MAFLD with high accuracy (AUC 0.789, 95% CI: 0.721-0.858), which was enhanced with the addition of cirrhosis to the model (AUC 0.855, 95% CI: 0.793-0.917). In particular, the presence of these metabolites was associated with cirrhosis in the MAFLD subgroup (p < 0.001). When considering the HCC cohort alone, the metabolic signature was an independent predictor of overall survival (HR 1.42, 95% CI: 1.09-1.83, p < 0.01). Conclusion: These exploratory findings reveal a metabolic signature in serum which is capable of accurately detecting the presence of HCC on a background of MAFLD. This unique serum signature will be taken forward for further investigation of diagnostic performance as biomarker of early stage HCC in patients with MAFLD in the future.

Sorafenib increases cytochrome P450 lipid metabolites in patient with hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a leading cause of cancer death, and medical treatment options are limited. The multikinase inhibitor sorafenib was the first approved drug widely used for systemic therapy in advanced HCC. Sorafenib might affect polyunsaturated fatty acids (PUFA)-derived epoxygenated metabolite levels, as it is also a potent inhibitor of the soluble epoxide hydrolase (sEH), which catalyzes the conversion of cytochrome-P450 (CYP)-derived epoxide metabolites derived from PUFA, such as omega-6 arachidonic acid (AA) and omega-3 docosahexaenoic acid (DHA), into their corresponding dihydroxy metabolites. Experimental studies with AA-derived epoxyeicosatrienoic acids (EETs) have shown that they can promote tumor growth and metastasis, while DHA-derived 19,20-epoxydocosapentaenoic acid (19,20-EDP) was shown to have anti-tumor activity in mice. In this study, we found a significant increase in EET levels in 43 HCC patients treated with sorafenib and a trend towards increased levels of DHA-derived 19,20-EDP. We demonstrate that the effect of sorafenib on CYP- metabolites led to an increase of 19,20-EDP and its dihydroxy metabolite, whereas DHA plasma levels decreased under sorafenib treatment. These data indicate that specific supplementation with DHA could be used to increase levels of the epoxy compound 19,20-EDP with potential anti-tumor activity in HCC patients receiving sorafenib therapy.

Delivery of biannual ultrasound surveillance for individuals with cirrhosis and cured hepatitis C in the UK.

BACKGROUND: Previous studies show the uptake of biannual ultrasound (US) surveillance in patients with cirrhosis is suboptimal. Here, our goal was to understand in broader terms how surveillance is being delivered to cirrhosis patients with cured hepatitis C in the UK. METHODS: Hepatitis C cirrhosis patients achieving a sustained viral response (SVR) to antiviral therapies were identified from the national Hepatitis-C-Research-UK resource. Data on (i) liver/abdominal US examinations, (ii) HCC diagnoses, and (iii) HCC curative treatment were obtained through record-linkage to national health registries. The rate of US uptake was calculated by dividing the number of US episodes by follow-up time. RESULTS: A total of 1908 cirrhosis patients from 31 liver centres were followed for 3.8 (IQR: 3.4-4.9) years. Overall, 10 396 liver/abdominal USs were identified. The proportion with biannual US was 19% in the first 3 years after SVR and 9% for all follow-up years. Higher uptake of biannual US was associated with attending a liver transplant centre; older age and cirrhosis decompensation. Funnel plot analysis indicated significant inter-centre variability in biannual US uptake, with 6/29 centres outside control limits. Incident HCC occurred in 133 patients, of which 49/133 (37%) were treated with curative intent. The number of US episodes in the two years prior to HCC diagnosis was significantly associated with higher odds of curative-intent treatment (aOR: 1.53; 95% CI: 1.12-2,09; p = .007). CONCLUSIONS: This study provides novel data on the cascade of care for HCC in the UK. Our findings suggest biannual US is poorly targeted, inefficient and is not being delivered equitably to all patients.

Current Status and Medicinal Prominence of Arnebia euchroma (Ratanjot): A Critically Endangered Plant of Trans-Himalayan Region.

Trans-Himalayan region has been a major component of the India's opulent medicinal plant heritage that encompasses numerous critically endangered plant species. Arnebia euchroma (Royle ex Benth.) Johnston (common name: Ratanjot), a Trans- Himalayan native, is amongst them, and it belongs to the family Boraginaceae. Ratanjot has long been used as a colourant in food and cosmetics besides a major ingredient of traditional remedies prescribed for curing mild constipation, dermatitis, frostbite, and eczema like health disorders. Though principally harvested for its roots, almost all the parts of this plant have been used in pharmaceutical products, food, dyes and beverages since prehistoric times. Its roots are a rich source of naphthoquinone pigment(s) mainly shikonin, acetylshikonin and deoxyshikonin, accountable for its medicinal value as antimicrobial, wound healing, anti-inflammatory, anticancer, and antioxidant agent(s). Considering the medicinal importance and critically endangered status of this taxon, the need of the hour is to conserve and propagate it for supplying sufficient raw materials for its commercial exploitation.

Genetic variation in TERT modifies the risk of hepatocellular carcinoma in alcohol-related cirrhosis: results from a genome-wide case-control study.

OBJECTIVE: Hepatocellular carcinoma (HCC) often develops in patients with alcohol-related cirrhosis at an annual risk of up to 2.5%. Some host genetic risk factors have been identified but do not account for the majority of the variance in occurrence. This study aimed to identify novel susceptibility loci for the development of HCC in people with alcohol related cirrhosis. DESIGN: Patients with alcohol-related cirrhosis and HCC (cases: n=1214) and controls without HCC (n=1866), recruited from Germany, Austria, Switzerland, Italy and the UK, were included in a two-stage genome-wide association study using a case-control design. A validation cohort of 1520 people misusing alcohol but with no evidence of liver disease was included to control for possible association effects with alcohol misuse. Genotyping was performed using the InfiniumGlobal Screening Array (V.24v2, Illumina) and the OmniExpress Array (V.24v1-0a, Illumina). RESULTS: Associations with variants rs738409 in PNPLA3 and rs58542926 in TM6SF2 previously associated with an increased risk of HCC in patients with alcohol-related cirrhosis were confirmed at genome-wide significance. A novel locus rs2242652(A) in TERT (telomerase reverse transcriptase) was also associated with a decreased risk of HCC, in the combined meta-analysis, at genome-wide significance (p=6.41×10-9, OR=0.61 (95% CI 0.52 to 0.70). This protective association remained significant after correction for sex, age, body mass index and type 2 diabetes (p=7.94×10-5, OR=0.63 (95% CI 0.50 to 0.79). Carriage of rs2242652(A) in TERT was associated with an increased leucocyte telomere length (p=2.12×10-44). CONCLUSION: This study identifies rs2242652 in TERT as a novel protective factor for HCC in patients with alcohol-related cirrhosis.

Corrigendum: Sorafenib increases cytochrome P450 lipid metabolites in patient with hepatocellular carcinoma.

[This corrects the article DOI: 10.3389/fphar.2023.1124214.].

Neutrophil-to-Lymphocyte and Platelet-to-Lymphocyte Ratios as Prognostic Biomarkers in Unresectable Hepatocellular Carcinoma Treated with Atezolizumab plus Bevacizumab.

Systemic inflammation is a key risk factor for hepatocellular carcinoma (HCC) progression and poor outcomes. Inflammatory markers such as the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) may have prognostic value in HCC treated with standard of care atezolizumab plus bevacizumab (Atezo-Bev). We conducted a multicenter, international retrospective cohort study of patients with unresectable HCC treated with Atezo-Bev to assess the association of NLR and PLR with overall survival (OS), progression-free survival (PFS), and objective response rates. Patients with NLR ≥ 5 had a significantly shorter OS (9.38 vs. 16.79 months, p < 0.001) and PFS (4.90 vs. 7.58 months, p = 0.03) compared to patients with NLR < 5. NLR ≥ 5 was an independent prognosticator of worse OS (HR 2.01, 95% CI 1.22−3.56, p = 0.007) but not PFS. PLR ≥ 300 was also significantly associated with decreased OS (9.38 vs. 15.72 months, p = 0.007) and PFS (3.45 vs. 7.11 months, p = 0.04) compared to PLR < 300, but it was not an independent prognosticator of OS or PFS. NLR and PLR were not associated with objective response or disease control rates. NLR ≥ 5 independently prognosticated worse survival outcomes and is worthy of further study and validation.

Impact of NAFLD on clinical outcomes in hepatocellular carcinoma treated with sorafenib: an international cohort study.

Background: The impact of nonalcoholic fatty liver disease (NAFLD) on overall survival (OS), treatment response and toxicity in patients with hepatocellular carcinoma (HCC) treated with sorafenib is unknown. We examined the impact of NAFLD on survival and toxicity in an international cohort of patients receiving sorafenib. Methods: Clinical and demographic data were collected from patients consecutively treated at specialist centres in Europe and North America. The impact of NAFLD on OS, sorafenib-specific survival and toxicity compared with other aetiologies of liver disease using multivariable Cox-proportional hazards and logistic regression modelling was assessed. Results: A total of 5201 patients received sorafenib; 183 (3.6%) had NAFLD-associated HCC. NAFLD-associated HCC patients were more likely to be older women (median age 65.8 versus 63.0 years, p < 0.01 and 10.4% versus 2.3%, < 0.01), with a median body mass index (BMI) of 29.4. After controlling for known prognostic factors, no difference in OS in patients with or without NAFLD was observed [hazard ratio (HR): 0.99, 95% confidence interval (CI): 0.84-1.18, p = 0.98]. NAFLD-associated patients had more advanced stage HCC when they commenced sorafenib [Barcelona Clinic Liver Class (BCLC) C/D 70.9% versus 58.9%, p < 0.01] and were more likely to be commenced on a lower starting dose of sorafenib (51.4 versus 36.4%, p < 0.01). There was no difference in sorafenib-specific survival between NAFLD and other aetiologies (HR: 0.96, 95% CI: 0.79-1.17, p = 0.96). Adverse events were similar between NAFLD and non-NAFLD HCC groups, including rates of greater than grade 2 hypertension (6.3% versus 5.8%, p = 1.00). Conclusion: Survival in HCC does not appear to be influenced by the presence of NAFLD. NAFLD-associated HCC derive similar clinical benefit from sorafenib compared with other aetiologies.

Epigenetic potentiation of somatostatin-2 by guadecitabine in neuroendocrine neoplasias as a novel method to allow delivery of peptide receptor radiotherapy.

BACKGROUND: Somatostatin receptor-2 (SSTR2) is expressed on cell surface of neuroendocrine neoplasias; its presence is exploited for the delivery of peptide receptor radionuclide therapy (PRRT). Patients with no or low expression of SSTR2 are not candidates for PRRT. SSTR2 promotor undergoes epigenetic modification, known to regulate gene expression. We investigated whether the demethylation agent, guadecitabine, could enhance the expression of SSTR2 in NET models, using radioligand uptake/PET imaging as a biomarker of epigenetic modification. METHODS: The effects of guadecitabine on the transcriptional, translational, and functional regulation of SSTR2 both in vitro and in vivo using low (QGP-1) and high (BON-1) methylated neuroendocrine neoplasia models was characterised. Promotor region methylation profiling of clinical samples (n = 61) was undertaken. Safety of combination guadecitabine and PRRT was assessed in vivo. RESULTS: Pyrosequencing of cell lines illustrated differential methylation indices - BON: 1 94%, QGP: 1 21%. Following guadecitabine treatment, a dose-dependent increase in SSTR2 in BON-1 at a transcriptional, translational, and functional levels using the SSTR2-directed radioligand, 18F-FET-ßAG-TOCA ([18F]-FETO) (150% increase [18F]-FETO uptake, p < 0.05) was observed. In vivo, guadecitabine treatment resulted in a 70% increase in [18F]-FETO uptake in BON-1 tumour models compared models with low baseline percentage methylation (p < 0.05). No additive toxicity was observed with the combination treatment of PRRT and guadecitabine in vivo. Methylation index in clinical samples was 10.5% compared to 5.2% in controls (p = 0.03) and correlated with SSTR2 expression (Wilcoxon rank sign -3.75,p < 0.01). CONCLUSION: Guadecitabine increases SSTR2 expression both in vitro and in vivo. The combination of demethylation agents with PRRT warrants further investigation.