Definitive Stereotactic Body Radiation Therapy in Early-Stage Solitary Hepatocellular Carcinoma: An Australian Multi-Institutional Review of Outcomes.

AIMS: Standard curative options for early-stage, solitary hepatocellular carcinoma (HCC) are often unsuitable due to liver dysfunction, comorbidities and/or tumour location. Stereotactic body radiation therapy (SBRT) has shown high rates of local control in HCC; however, limited data exist in the treatment-naïve, curative-intent setting. We report the outcomes of patients with solitary early-stage HCC treated with SBRT as first-line curative-intent therapy. MATERIALS AND METHODS: A multi-institutional retrospective study of treatment-naïve patients with Barcelona Clinic Liver Cancer stage 0/A, solitary ≤5 cm HCC, Child-Pugh score (CPS) A liver function who underwent SBRT between 2010 and 2019 as definitive therapy. The primary end point was freedom from local progression. Secondary end points were progression-free survival, overall survival, rate of treatment-related clinical toxicities and change in CPS >1. RESULTS: In total, 68 patients were evaluated, with a median follow-up of 20 months (range 3-58). The median age was 68 years (range 50-86); 54 (79%) were men, 62 (91%) had cirrhosis and 50 (74%) were Eastern Cooperative Oncology Group 0. The median HCC diameter was 2.5 cm (range 1.3-5) and the median prescription biologically effective dose with a tumour a/b ratio of 10 Gy (BED10) was 93 Gy (interquartile range 72-100 Gy). Two-year freedom from local progression, progression-free survival and overall survival were 94.3% (95% confidence interval 86.6-100%), 59.5% (95% confidence interval 46.3-76.4%) and 88% (95% confidence interval 79.2-97.6%), respectively. Nine patients (13.2%) experienced grade ≥2 treatment-related clinical toxicities. A rise >1 in CPS was observed in six cirrhotic patients (9.6%). CONCLUSION: SBRT is an effective and well-tolerated option to consider in patients with solitary, early-stage HCC. Prospective, randomised comparative studies are warranted to further refine its role as a first-line curative-intent therapy.

Plant-based milk: unravel the changes of the antioxidant index during processing and storage - a review.

As a nutrient rich emulsion extracted from plant materials, plant-based milk (PBM) has been the latest trend and hot topic in the food industry due to the growing awareness of consumers toward plant-based products in managing the environmental (carbon footprint and land utility), ethical (animal well-fare) and societal (health-conscious) issues. There have been extensive studies and reviews done to discuss the distinct perspective of PBM including its production, health effects and market acceptance. However, not much has been emphasized on the valuable antioxidants present in PBM which is one of the attributes making them stand apart from dairy milk. The amounts of antioxidants in PBM are important. They offered tremendous health benefits in maintaining optimum health and reducing the risk of various health disorders. Therefore, enhancing the extraction of antioxidants and preserving their activity during production and storage is important. However, there is a lack of a comprehensive review of how these antioxidants changes in response to different processing steps involved in PBM production. Presumably, antioxidants in PBM could be potentially lost due to thermal degradation, oxidation or leaching into processing water. Hence, this paper aims to fill the gaps by addressing an extensive review of how different production steps (germination, roasting, soaking, blanching, grinding and filtration, and microbial inactivation) affect the antioxidant content in PBM. In addition, the effect of different microbial inactivation treatments (thermal or non-thermal processing) on the alteration of antioxidant in PBM was also highlighted. This paper can provide useful insight for the industry that aims in selecting suitable processing steps to produce PBM products that carry with them a health declaration.

Implementing a systematic care pathway for management of dysphagia after cardiothoracic surgery.

OBJECTIVES: This longitudinal quality improvement study explored the impact of a new multidisciplinary dysphagia care pathway on swallow screening referrals, patient journeys and swallow outcomes in patients after cardiac surgery. RESEARCH METHODOLOGY: The new dysphagia care pathway consisted of i) nurse chart review triaging using established risk factors, ii) nurse swallow screening (including a cough reflex test and water swallow test) and iii) rapid referral routes to speech pathology. All patients referred for swallow screening in 2020 after the commencement of the new dysphagia care pathway were included (n = 114). Data was compared to two historical, published data sets at the research site (n-41 in 2012-2013 and n = 121 in 2013-2016). SETTING: Cardiovascular intensive care unit. RESULTS: 52% failed chart review and 29% failed cough reflex test. All patients who passed chart review and cough reflex test returned to a normal diet without need for speech pathology referral. Silent aspiration rates were high in those who failed chart review and the cough reflex test (42%, 43% respectively). For those who received a swallow screen, enteral feeding rates were 70% on first assessment and 27% by discharge from the unit in historical data (2013-2016). In comparison, in 2020, enteral feeding rates were 44% and 8% respectively. CONCLUSIONS: Referrals for nurse swallow screening and speech pathology increased following the introduction of the care pathway. There has been a reduction in enteral feeding rates and length of enteral feeding at discharge. High rates of silent aspiration in those who fail screening suggests stepwise nurse dysphagia screening successfully picks up at-risk patients.

The cost-effectiveness of banning highly hazardous pesticides to prevent suicides due to pesticide self-ingestion across 14 countries: an economic modelling study.

BACKGROUND: Reducing suicides is a key Sustainable Development Goal target for improving global health. Highly hazardous pesticides are among the leading causes of death by suicide in low-income and middle-income countries. National bans of acutely toxic highly hazardous pesticides have led to substantial reductions in pesticide-attributable suicides across several countries. This study evaluated the cost-effectiveness of implementing national bans of highly hazardous pesticides to reduce the burden of pesticide suicides. METHODS: A Markov model was developed to examine the costs and health effects of implementing a national ban of highly hazardous pesticides to prevent suicides due to pesticide self-poisoning, compared with a null comparator. We used WHO cost-effectiveness and strategic planning (WHO-CHOICE) methods to estimate pesticide-attributable suicide rates for 100 years from 2017. Country-specific costs were obtained from the WHO-CHOICE database and denominated in 2017 international dollars (I$), discounted at a 3% annual rate, and health effects were measured in healthy life-years gained (HLYGs). We used a demographic projection model beginning with the country population in the baseline year (2017), split by 1-year age group and sex. Country-specific data on overall suicide rates were obtained for 2017 by age and sex from the Global Burden of Disease Study 2017 Data Resources. The analysis involved 14 countries spanning low-income to high-income settings, and cost-effectiveness ratios were analysed at the country-specific level and aggregated according to country income group and the proportion of suicides due to pesticides. FINDINGS: Banning highly hazardous pesticides across the 14 countries studied could result in about 28 000 (95% uncertainty interval [UI] 24 000-32 000) fewer suicide deaths each year at an annual cost of I$0·007 per capita (95% UI 0·006-0·008). In the population-standardised results for the base case analysis, national bans produced cost-effectiveness ratios of $94 per HLYG (95% UI 73-123) across low-income and lower-middle-income countries and $237 per HLYG (95% UI 191-303) across upper-middle-income and high-income countries. Bans were more cost-effective in countries where a high proportion of suicides are attributable to pesticide self-poisoning, reaching a cost-effectiveness ratio of $75 per HLYG (95% UI 58-99) in two countries with proportions of more than 30%. INTERPRETATION: National bans of highly hazardous pesticides are a potentially cost-effective and affordable intervention for reducing suicide deaths in countries with a high burden of suicides attributable to pesticides. However, our study findings are limited by imperfect data and assumptions that could be improved upon by future studies. FUNDING: WHO.

Enteropathy-associated T-cell Lymphoma (EATL) with intracranial metastasis : a rare and dismal condition.

BACKGROUND: Enteropathy-associated T-cell lymphoma (EATL) is a rare type of gastrointestinal non-Hodgkin's Lymphoma. EATL with intracranial metastasis is even rarer. We report a case of EATL with intracranial metastasis. CASE PRESENTATION: A 36-years old man presented with five weeks history of intractable diarrhea. Colonoscopy was normal, but abdominal computed tomography (CT) scan revealed mural thickening at duodenojejunal junction, and subsequent jejunofiberoscopy showed a circumferential ulceration at the jejunum. Histo-immunopathology confirmed the diagnosis of enteropathyassociated T-cell lymphoma (EATL) type II. His disease course proved to be aggressive and refractory to standard front-line chemotherapy, and eventually progressed through second-line salvage regimen with CNS and intracranial involvement. He died nine months after the initial diagnosis. CONCLUSION: EATL with brain metastasis is a very rare occurrence with dismal prognosis.

Immunomagnetic Reduction Assay on Des-Gamma-Carboxy Prothrombin for Screening of Hepatocellular Carcinoma.

The accredited biomarker alpha-fetoprotein (AFP) offers limited sensitivity and specificity in the early detection of hepatocellular carcinoma (HCC). To improve the screening performance, des-gamma-carboxy prothrombin (DCP) has been identified as another promising biomarker of HCC, combined with AFP biomarkers. The results of the commercial optical enzyme-linked immunosorbent assay (ELISA) kit easily have the interference problem due to the optical methodology. The immunomagnetic reduction (IMR) assay based on the magnetic measurement was utilized to assay DCP biomarkers without the excellent antiinterference performances. A DCP magnetic reagent, composed of iron-oxide (Fe3O4 ) magnetic nanoparticles coated with anti-DCP antibodies solved in phosphoryl-buffer solution, was synthesized and characterized. In the test of standard DCP antigens, superior antiinterference and sensitivity than optical ELISA were proved. In the animal test, the results indicate good agreement between the IMR assay findings and the tumor sizes of HCC rats at all time points after the HCC implantation. The feasibility of the developed DCP magnetic reagent with the IMR for the detection of DCP is verified, and demonstrates the high potential for future clinical applications.

Stevens-Johnson syndrome and toxic epidermal necrolysis in patients with malignancies.

BACKGROUND: Malignancy is known to be associated with an increased mortality rate in patients with Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). However, risk factors contributing to the poor prognosis of patients with SJS/TEN with malignancies remain undefined. OBJECTIVES: To explore the potential involvement of malignancy and its related factors contributing to the poor outcome of SJS/TEN, in a retrospective study. METHODS: In total 517 patients with SJS/TEN were enrolled. Forty-seven who sustained various types of malignancies were analysed for numerous malignancy-related factors, including cancer types, clinical stages and chemotherapies given or not before the onset of SJS/TEN. RESULTS: We found that the mortality rate of patients with SJS/TEN with malignancies was higher than that of patients without malignancies (32%, 15/47 vs. 8·5%, 40/470, respectively) (P < 0·001). The use of phenytoin was significantly higher in the malignancy group. The presence of hepatocellular carcinoma (80%, four of five; P < 0·001; odds ratio 43) and colorectal cancer (67%, two of three; P = 0·022; odds ratio 21·5) significantly increased the death rate of patients with SJS/TEN, whereas lung cancer and urothelial carcinoma did not. Patients who had received ongoing or recent chemotherapy showed higher mortality than those without chemotherapy (P = 0·022; odds ratio 4·95). Furthermore, among the 47 patients with SJS/TEN with malignancies, lower serum albumin, haemoglobin and platelet count were detected in the deceased patients than in the surviving patients before the onset of SJS/TEN. CONCLUSIONS: Our results suggest that several factors related to malignancies, such as specific cancer types, chemotherapy and malnutrition, may contribute to poor prognosis in patients with malignancies developing SJS/TEN.

Special Issue on "Analytical Methods for Oxidized Biomolecules and Antioxidants" The use of isoprostanoids as biomarkers of oxidative damage, and their role in human dietary intervention studies.

Isoprostanoids are a group of non-enzymatic oxidized lipids from polyunsaturated fatty acids. They are commonly used as biomarkers for oxidative damage, to assess in vivo lipid peroxidation in diseases related to the vascular system and neurodegeneration. Currently, there is a mismatch with the outcome in the use of these biomarkers in intervention studies, particularly when testing the effect of antioxidants such as vitamins C and E, or zinc, or a cocktail of these, with other food components. Much of this is because the biomarkers, the method of measurement, and the duration of supplementation are unsuitable. In this review, we will highlight the formation of isoprostanoids from their respective fatty acids, and their application as biomarkers for oxidative damage in vivo, considering human dietary intervention studies evaluating plasma and urine, using mass spectrometry techniques.

Disruption of the gastroesophageal junction by central obesity and waist belt: role of raised intra-abdominal pressure.

Obesity is a major reason for the recent increase in incidence of reflux disease and cancers at the distal esophagus and gastroesophageal junction (GOJ) and is mediated through a rise in the intra-abdominal pressure (IAP) but the exact mechanisms are unclear. Raised IAP from obesity and with application of waist belt produces mechanical distortion of the GOJ through formation of partial hiatus hernia. Even though there is no trans-sphincteric acid reflux, there is increased ingress of acid into the lower sphincter (intra-sphincteric reflux) as a consequence of raised IAP. In addition, short segment acid reflux is more evident in obese subjects with a belt on. Acid pocket is also enlarged in hiatus hernia, and acts as a reservoir of acid available to reflux whenever the sphincter fails. Above mechanisms may explain the common occurrence of cardiac lengthening and inflammation found in asymptomatic obese subjects. The inflamed cardia is also immunohistochemically similar to non-intestinal Barrett's mucosa, which is of etiological importance for cancers at the GOJ. Interventions that can reduce the mechanical distortion and acid exposure at the GOJ, including diet, exercise, drugs, sphincter augmentation therapy, and surgery, are clinically relevant in the treatment of gastroesophageal reflux disease but more data are needed whether if these strategies are also effective in preventing cancer. As a conclusion, raised IAP produces silent mechanical disruption of the GOJ, which may explain the high occurrence of cancers in this region and it is potentially reversible with early interventions.

A short review of basic head and neck interventional procedures in a general radiology department.

Image-guided interventional procedures provide a safe way to diagnose and treat a variety of head and neck abnormalities. The procedure time is usually short, and most procedures can be performed on an outpatient basis. Knowledge about strengths and weaknesses, efficacy, potential complications, and pitfalls of these procedures allows the best treatment to be chosen for a particular lesion type. This review discusses some of the commonly performed interventional radiology procedures in a general radiology department in the management of patients with neoplastic diseases in the head and neck region.

CREB-binding protein (CBP) regulates ß-adrenoceptor (ß-AR)-mediated apoptosis.

Catecholamines regulate the ß-adrenoceptor/cyclic AMP-regulated protein kinase A (cAMP/PKA) pathway. Deregulation of this pathway can cause apoptotic cell death and is implicated in a range of human diseases, such as neuronal loss during aging, cardiomyopathy and septic shock. The molecular mechanism of this process is, however, only poorly understood. Here we demonstrate that the ß-adrenoceptor/cAMP/PKA pathway triggers apoptosis through the transcriptional induction of the pro-apoptotic BH3-only Bcl-2 family member Bim in tissues such as the thymus and the heart. In these cell types, the catecholamine-mediated apoptosis is abrogated by loss of Bim. Induction of Bim is driven by the transcriptional co-activator CBP (CREB-binding protein) together with the proto-oncogene c-Myc. Association of CBP with c-Myc leads to altered histone acetylation and methylation pattern at the Bim promoter site. Our findings have implications for understanding pathophysiology associated with a deregulated neuroendocrine system and for developing novel therapeutic strategies for these diseases.

Incidence and outcomes of pregnancy-associated cancer in Australia, 1994-2008: a population-based linkage study.

OBJECTIVE: To determine trends in pregnancy-associated cancer and associations between maternal cancer and pregnancy outcomes. DESIGN: Population-based cohort study. SETTING: New South Wales, Australia, 1994-2008. POPULATION: A total of 781 907 women and their 1 309 501 maternities. METHODS: Cancer and maternal information were obtained from linked cancer registry, birth and hospital records for the entire population. Generalised estimating equations with a logit link were used to examine associations between cancer risk factors and pregnancy outcomes. MAIN OUTCOME MEASURES: Incidence of pregnancy-associated cancer (diagnosis during pregnancy or within 12 months of delivery), maternal morbidities, preterm birth, and small- and large-for-gestational-age (LGA). RESULTS: A total of 1798 new cancer diagnoses were identified, including 499 during pregnancy and 1299 postpartum. From 1994 to 2007, the crude incidence rate of pregnancy-associated cancer increased from 112.3 to 191.5 per 100 000 maternities (P < 0.001), and only 14% of the increase was explained by increasing maternal age. Cancer diagnosis was more common than expected in women aged 15-44 years (observed-to-expected ratio 1.49; 95% CI 1.42-1.56). Cancers were predominantly melanoma (33.3%) and breast cancer (21.0%). Women with cancer diagnosed during pregnancy had high rates of labour induction (28.5%), caesarean section (40.0%) and planned preterm birth (19.7%). Novel findings included a cancer association with multiple pregnancies (adjusted odds ratio 1.52, 95% CI 1.13-2.05) and LGA (aOR 1.47, 95% CI 1.14-1.89). CONCLUSIONS: Pregnancy-associated cancers have increased, and this increase is only partially explained by increasing maternal age. Pregnancy increases women's interaction with health services and the possibility for diagnosis, but may also influence tumour growth.

Cre transgene results in global attenuation of the cAMP/PKA pathway.

Use of the cre transgene in in vivo mouse models to delete a specific 'floxed' allele is a well-accepted method for studying the effects of spatially or temporarily regulated genes. During the course of our investigation into the effect of cyclic adenosine 3',5'-monophosphate-dependent protein kinase A (PKA) expression on cell death, we found that cre expression either in cultured cell lines or in transgenic mice results in global changes in PKA target phosphorylation. This consequently alters gene expression profile and changes in cytokine secretion such as IL-6. These effects are dependent on its recombinase activity and can be attributed to the upregulation of specific inhibitors of PKA (PKI). These results may explain the cytotoxicity often associated with cre expression in many transgenic animals and may also explain many of the phenotypes observed in the context of Cre-mediated gene deletion. Our results may therefore influence the interpretation of data generated using the conventional cre transgenic system.

The Kiss2 receptor (Kiss2r) gene in Southern Bluefin Tuna, Thunnus maccoyii and in Yellowtail Kingfish, Seriola lalandi - functional analysis and isolation of transcript variants.

The kisspeptin system plays an essential role in reproductive function in vertebrates, particularly in the onset of puberty. We investigated the kisspeptin system in two Perciform teleosts, the Southern Bluefin Tuna (SBT; Thunnus maccoyii), and the Yellowtail Kingfish (YTK; Seriola lalandi), by characterising their kisspeptin 2 receptor (Kiss2r) genes. In addition to the full length Kiss2r cDNA sequences, we have isolated from SBT and YTK a transcript variant that retained an intron. We have further obtained three ytkKiss2r transcript variants that contained deletions. In vitro functional analysis of the full length SBT and YTK Kiss2r showed higher response to Kiss2-10 than to Kiss1-10, with stronger transduction via PKC than PKA. The full length ytkKiss2r and two deletion variants were differentially expressed in the brain of male, but not in female, juvenile YTK treated with increasing doses of Kiss2-10 peptide. In the gonads, the expression level of the ytkKiss2r transcripts did not vary significantly either in the male or female fish. This is the first time that transcript variants of the Kiss2r gene that contain deletions and show responsiveness to treatments with kisspeptin have been reported in any teleost.

BCLAF1 is a radiation-induced H2AX-interacting partner involved in γH2AX-mediated regulation of apoptosis and DNA repair.

H2AX, a histone H2A variant, has a key role in the cellular response to DNA double-strand breaks (DSBs). H2AX senses DSBs through rapid serine 139 phosphorylation, concurrently leading to the formation of phospho-(γ)H2AX foci with various proteins. However, in the cells with different sensitivity to ionizing radiation (IR)-induced DSBs, still incomplete are those specific proteins selectively recruited by γH2AX to decide different cell fates. Because the abundance of γH2AX indicates the extent of DSBs, we first identified IR-induced dose-dependent H2AX-interacting partners and found that Bcl-2-associated transcription factor 1 (BCLAF1/Btf) showed enhanced association with γH2AX only under high-dose radiation. In acutely irradiated cells, BCLAF1 promoted apoptosis of irreparable cells through disturbing p21-mediated inhibition of Caspase/cyclin E-dependent, mitochondrial-mediated pathways. Meanwhile, BCLAF1 co-localized with γH2AX foci in nuclei and stabilized the Ku70/DNA-PKcs complex therein, facilitating non-homologous end joining (NHEJ)-based DSB repair in surviving cells. In tumor cells, BCLAF1 was intrinsically suppressed, leading to formation of anti-apoptotic Ku70-Bax complexes and disruption of Ku70/DNA-PKcs complexes, all of which contribute to tumor-associated apoptotic resistance and cell survival with defective NHEJ DNA repair. For the first time, our studies reveal that, based on the extent of DNA damage, BCLAF1 is involved in the γH2AX-mediated regulation of apoptosis and DNA repair, and is a γH2AX-interacting tumor suppressor.

Kinetics of transient hiatus hernia during transient lower esophageal sphincter relaxations and swallows in healthy subjects.

BACKGROUND: Proximal displacement of the gastro-esophageal junction (GEJ) is present in hiatus hernia but also occurs transiently during transient lower esophageal sphincter relaxations (TLESRs) and swallows. Using a novel magnetic-based technique we have performed detailed examination of the GEJ movement during TLESRs and swallows in healthy subjects. METHODS: In 12 subjects, a magnet was endoscopically clipped to the GEJ and combined assembly of Hall-Effect locator probe and 36 channel high-resolution manometer passed nasally. After a test meal the subjects were studied for 90 min. KEY RESULTS: The median amplitude of proximal movement of GEJ during TLESRs was 4.3 cm (1.6-8.8 cm) and this was substantially greater than during swallowing at 1.2 cm (0.4-2.7 cm), P = 0.002. With both TLESRs and swallows proximal GEJ movement coincided with lower esophageal sphincter (LES) relaxation and return to its original position occurred 4 s after return of LES tone. Kinetic modeling of the movement of the GEJ during TLESRs indicated two return phases with the initial return phase having the greater velocity (0.9 cm s(-1) ) and being strongly correlated with amplitude of proximal movement (r = 0.8, P < 0.001). CONCLUSIONS & INFERENCES: The marked proximal GEJ migration during TLESRs represents very severe herniation of the GEJ. The rapid initial return of the GEJ following TLESRs when the crural diaphragm is relaxed and its correlation with amplitude suggest it is due to elastic recoil of the phreno-esophageal ligament. The marked stretching of the phreno-esophageal ligament during TLESRs may contribute to its weakening and development of established hiatus hernia.