Initial Trans-Arterial Chemo-Embolisation (TACE) Is Associated with Similar Survival Outcomes as Compared to Upfront Percutaneous Ablation Allowing for Follow-Up Treatment in Those with Single Hepatocellular Carcinoma (HCC) ≤ 3 cm: Results of a Real-World Propensity-Matched Multi-Centre Australian Cohort Study.

Percutaneous ablation is recommended in Barcelona Clinic Liver Cancer (BCLC) stage 0/A patients with HCC ≤3 cm as a curative treatment modality alongside surgical resection and liver transplantation. However, trans-arterial chemo-embolisation (TACE) is commonly used in the real-world as an initial treatment in patients with single small HCC in contrast to widely accepted clinical practice guidelines which typically describe TACE as a treatment for intermediate-stage HCC. We performed this real-world propensity-matched multi-centre cohort study in patients with single HCC ≤ 3 cm to assess for differences in survival outcomes between those undergoing initial TACE and those receiving upfront ablation. Patients with a new diagnosis of BCLC 0/A HCC with a single tumour ≤3 cm first diagnosed between 1 January 2016 and 31 December 2020 who received initial TACE or ablation were included in the study. A total of 348 patients were included in the study, with 147 patients receiving initial TACE and 201 patients undergoing upfront ablation. After propensity score matching using key covariates, 230 patients were available for analysis with 115 in each group. There were no significant differences in overall survival (log-rank test p = 0.652) or liver-related survival (log-rank test p = 0.495) over a median follow-up of 43 months. While rates of CR were superior after ablation compared to TACE as a first treatment (74% vs. 56%, p < 0.004), there was no significant difference in CR rates when allowing for further subsequent treatments (86% vs. 80% p = 0.219). In those who achieved CR, recurrence-free survival and local recurrence-free survival were similar (log rank test p = 0.355 and p = 0.390, respectively). Our study provides valuable real-world evidence that TACE when offered with appropriate follow-up treatment is a reasonable initial management strategy in very early/early-stage HCC, with similar survival outcomes as compared to those managed with upfront ablation. Further work is needed to better define the role for TACE in BCLC 0/A HCC.

Different Patterns of Care and Survival Outcomes in Transplant-Centre Managed Patients with Early-Stage HCC: Real-World Data from an Australian Multi-Centre Cohort Study.

The management of early-stage hepatocellular carcinoma (HCC) is complex, with multiple treatment strategies available. There is a paucity of literature regarding variations in the patterns of care and outcomes between transplant and non-transplant centres. We conducted this real-world multi-centre cohort study in two liver cancer referral centres with an integrated liver transplant program and an additional eight non-transplant HCC referral centres across Australia to identify variation in patterns of care and key survival outcomes. Patients with stage Barcelona Clinic Liver Cancer (BCLC) 0/A HCC, first diagnosed between 1 January 2016 and 31 December 2020, who were managed at a participating site, were included in the study. Patients were excluded if they had a history of prior HCC or if they received upfront liver transplantation. A total of 887 patients were included in the study, with 433 patients managed at a liver cancer centre with a transplant program (LTC) and 454 patients managed at a non-transplant centre (NTC). Management at an LTC did not significantly predict allocation to resection (adjusted OR 0.75, 95% CI 0.50 to 1.11, p = 0.148). However, in those not receiving resection, LTC and NTC patients were systematically managed differently, with LTC patients five times less likely to receive upfront ablation than NTC patients (adjusted OR 0.19, 95% CI 0.13 to 0.28, p < 0.001), even after adjusting for tumour burden, as well as for age, gender, liver disease aetiology, liver disease severity, and medical comorbidities. LTCs exhibited significantly higher proportions of patients undergoing TACE for every tumour burden category, including those with a single tumour measuring 2 cm or less (p < 0.001). Using multivariable Cox proportional hazards analysis, management at a transplant centre was associated with reduced all-cause mortality (adjusted HR 0.71, 95% CI 0.51 to 0.98, p = 0.036), and competing-risk regression analysis, considering liver transplant as a competing event, demonstrated a similar reduction in risk (adjusted HR 0.70, 95% CI 0.50 to 0.99, p = 0.041), suggesting that the reduced risk of death is not fully explained by higher rates of transplantation. Our study highlights systematic differences in HCC care between large volume liver transplant centres and other sites, which has not previously been well-described. Further work is needed to better define the reasons for differences in treatment allocation and to aim to minimise unwarranted treatment variation to maximise patient outcomes across Australia.

Improved Survival Outcomes with Surgical Resection Compared to Ablative Therapy in Early-Stage HCC: A Large, Real-World, Propensity-Matched, Multi-Centre, Australian Cohort Study.

The optimal treatment approach in very-early and early-stage hepatocellular carcinoma (HCC) is not precisely defined, and there is ambiguity in the literature around the comparative efficacy of surgical resection versus ablation as curative therapies for limited disease. We performed this real-world propensity-matched, multi-centre cohort study to assess for differences in survival outcomes between those undergoing resection and those receiving ablation. Patients with Barcelona Clinic Liver Cancer (BCLC) 0/A HCC first diagnosed between 1 January 2016 and 31 December 2020 who received ablation or resection as initial treatment were included in the study. A total of 450 patients were included in the study from 10 major liver centres including two transplant centres. Following propensity score matching using key covariates, 156 patients were available for analysis with 78 in each group. Patients who underwent resection had significantly improved overall survival (log-rank test p = 0.023) and local recurrence-free survival (log rank test p = 0.027) compared to those who received ablation. Based on real-world data, our study supports the use of surgical resection in preference to ablation as first-line curative therapy in appropriately selected BCLC 0/A HCC patients.

Association between continuity and access in primary care: a retrospective cohort study.

BACKGROUND: Continuity of care is a tenet of primary care. Our objective was to explore the relation between a change in access to a primary care physician and continuity of care. METHODS: We conducted a retrospective cohort study among physicians in a primary care network in southwest Alberta who measured access consistently between 2009 and 2016. We used time to the third next available appointment as a measure of access to physicians. We calculated the provider and clinic continuity, discontinuity and emergency department use based on the physicians' own panels. Physicians who improved, worsened or maintained their level of access within a given year were assessed in multilevel models to determine the association with continuity of care at the physician and clinic levels and the emergency department. RESULTS: We analyzed data from 190 primary care physicians. Physicians with improved access increased provider continuity by 6.8% per year, reduced discontinuity by 2.1% per year, and decreased emergency department encounters by 78 visits per 1000 patients per year compared to physicians with stable access. Physicians with worsening access had a 6.2% decrease in provider continuity and an increased number of emergency department encounters (64 visits per 1000 panelled patients per year) compared to physicians with stable access. INTERPRETATION: Changes in access to primary care can affect whether patients seek care from their own physician, from another clinic or at the emergency department. Improving access by reducing the delay in obtaining an appointment with one's primary care physician may be one mechanism to improve continuity of care.

Sonographic grading of fetal intracardiac echogenic foci in a population at low risk of aneuploidy.

PURPOSE: We screened pregnant women at low risk of a fetal chromosomal abnormality for the presence of fetal intracardiac echogenic foci (ICEF) and graded those foci by using sonographic gain reduction. Our objectives were to determine the interobserver reliability of the technique and the association of ICEF, by grade, with fetal aneuploidy. METHODS: Pregnant women who were 18-35 years old, at low risk for fetal chromosomal abnormalities, and referred for targeted sonography at 16-24 weeks' menstrual age were eligible to participate. All patients whose fetuses had ICEF were offered fetal chromosomal analysis. The presence of ICEF was ascertained by an apical 4-chamber view of the fetal heart and graded independently by 2 examiners blinded to each other's assessment. Grading was based on the difference in echogenicity of the ICEF and the thoracic spine as the ultrasound gain was reduced; in grade 1, the ICEF image was lost before that of the thoracic spine; in grade 2, the ICEF and thoracic spine images disappeared at the same gain setting; and in grade 3, the thoracic spine image was lost before that of the ICEF. RESULTS: During the 6-month study period, 383 eligible women were examined, and ICEF were seen in 35 fetuses (9.1%): 25 (71.4%) in the left ventricle, 1 (2.9%) in the right ventricle, and 9 (25.7%) in both ventricles. ICEF grading was successfully performed in all 33 of the women with fetal ICEF who elected to participate. Twenty-one (63.6%) had grade 1, 9 (27.3%) had grade 2, and 3 (9.1%) had grade 3 ICEF. Interobserver agreement was noted in 27 (90.0%) of 30 available paired second-trimester observations (kappa = 0.8), indicating excellent agreement. Two fetuses (6.1%) with grade 1 ICEF but no other risk factors for aneuploidy had chromosomal abnormalities, as compared with 1 fetus (0.3%) in the control group, which had no ICEF (p = 0.02). CONCLUSIONS: Sonographic grading of ICEF is feasible and reliable. The presence of fetal ICEF in a population otherwise at low risk for aneuploidy seems to warrant the performance of fetal chromosomal analysis.

A vapor exposure model for neonatal mice.

Sulfur mustard (HD) is a vesicant compound that was first used as a chemical warfare agent in World War I. (Papirmeister et al. 1991). Numerous animal models have been used to study HD-induced vesication. In this article, we describe modifications of the vapor cup model of Mershon and colleagues (1990) to establish a new vapor cup model for use in neonatal mice. The need to develop this model resulted from the development of gene-targeted knockout mice that can be used to evaluate the function of specific genes and their contribution to HD-induced pathology. However, the knockouts are haired mice; therefore, it is necessary to perform vapor exposures on the pups prior to their growing hair. Neonatal mice were anesthetized with isofluorane inhalation and placed in sternal recumbency on a 37 degrees C isothermal pad to maintain body heat during exposure. The vapor cup consisted of a 1.5-mL microfuge tube cap (8 mm inside diameter) modified using a Dremel tool to contour its rim to better fit the curve of a mouse pups back. The inside of the cap was fitted with an 8-mm disk of Whatman #2 filter paper, and the rim of the cap was coated with a thin bead of Thomas Lubriseal grease. Ten muL of neat HD was placed on the filter paper disk, and the cup was immediately inverted and placed onto the back of an anesthetized mouse pup. Exposure times varied from 10 to 30 min. At 24 h postexposure, the mice were euthanized; the HD-exposed skin was removed and fixed in 10% neutral buffered formalin. Following a minimum of 24 h of formalin fixation, the skin sections were bisected across the exposed area. The sections were embedded in paraffin with the central straight-cut surfaces being the focus of histological evaluation. The amount of damage associated with the HD vapor cup exposure varied with time in a dose response fashion. Typical damage consisted of varying amounts of epidermal necrosis at the basal cell level, with occasional separation of epidermis from dermis (microvesication). In severe cases there was complete coagulation of the epidermis and no microvesication. This model should prove useful in identifying the biochemical mechanism of action of HD and ultimately aid in the evaluation of treatment compounds. It may also provide a relevant exposure model for other compounds for which the assessment of vapor-induced damage is necessitated.