A randomised controlled trial of Standard Of Care versus RadioAblaTion in Early Stage HepatoCellular Carcinoma (SOCRATES HCC).

BACKGROUND: Therapeutic options for early-stage hepatocellular carcinoma (HCC) in individual patients can be limited by tumor and location, liver dysfunction and comorbidities. Many patients with early-stage HCC do not receive curative-intent therapies. Stereotactic ablative body radiotherapy (SABR) has emerged as an effective, non-invasive HCC treatment option, however, randomized evidence for SABR in the first line setting is lacking. METHODS: Trans-Tasman Radiation Oncology Group (TROG) 21.07 SOCRATES-HCC is a phase II, prospective, randomised trial comparing SABR to other current standard of care therapies for patients with a solitary HCC ≤ 8 cm, ineligible for surgical resection or transplantation. The study is divided into 2 cohorts. Cohort 1 will compromise 118 patients with tumors ≤ 3 cm eligible for thermal ablation randomly assigned (1:1 ratio) to thermal ablation or SABR. Cohort 2 will comprise 100 patients with tumors > 3 cm up to 8 cm in size, or tumors ≤ 3 cm ineligible for thermal ablation, randomly assigned (1:1 ratio) to SABR or best other standard of care therapy including transarterial therapies. The primary objective is to determine whether SABR results in superior freedom from local progression (FFLP) at 2 years compared to thermal ablation in cohort 1 and compared to best standard of care therapy in cohort 2. Secondary endpoints include progression free survival, overall survival, adverse events, patient reported outcomes and health economic analyses. DISCUSSION: The SOCRATES-HCC study will provide the first randomized, multicentre evaluation of the efficacy, safety and cost effectiveness of SABR versus other standard of care therapies in the first line treatment of unresectable, early-stage HCC. It is a broad, multicentre collaboration between hepatology, interventional radiology and radiation oncology groups around Australia, coordinated by TROG Cancer Research. TRIAL REGISTRATION: anzctr.org.au, ACTRN12621001444875, registered 21 October 2021.

DNA Double Strand Break and Response Fluorescent Assays: Choices and Interpretation.

Accurately characterizing DNA double-stranded breaks (DSBs) and understanding the DNA damage response (DDR) is crucial for assessing cellular genotoxicity, maintaining genomic integrity, and advancing gene editing technologies. Immunofluorescence-based techniques have proven to be invaluable for quantifying and visualizing DSB repair, providing valuable insights into cellular repair processes. However, the selection of appropriate markers for analysis can be challenging due to the intricate nature of DSB repair mechanisms, often leading to ambiguous interpretations. This comprehensively summarizes the significance of immunofluorescence-based techniques, with their capacity for spatiotemporal visualization, in elucidating complex DDR processes. By evaluating the strengths and limitations of different markers, we identify where they are most relevant chronologically from DSB detection to repair, better contextualizing what each assay represents at a molecular level. This is valuable for identifying biases associated with each assay and facilitates accurate data interpretation. This review aims to improve the precision of DSB quantification, deepen the understanding of DDR processes, assay biases, and pathway choices, and provide practical guidance on marker selection. Each assay offers a unique perspective of the underlying processes, underscoring the need to select markers that are best suited to specific research objectives.

Nanoparticles Targeted to Fibroblast Activation Protein Outperform PSMA for MRI Delineation of Primary Prostate Tumors.

Accurate delineation of gross tumor volumes remains a barrier to radiotherapy dose escalation and boost dosing in the treatment of solid tumors, such as prostate cancer. Magnetic resonance imaging (MRI) of tumor targets has the power to enable focal dose boosting, particularly when combined with technological advances such as MRI-linear accelerator. Fibroblast activation protein (FAP) is overexpressed in stromal components of >90% of epithelial carcinomas. Herein, the authors compare targeted MRI of prostate specific membrane antigen (PSMA) with FAP in the delineation of orthotopic prostate tumors. Control, FAP, and PSMA-targeting iron oxide nanoparticles were prepared with modification of a lymphotropic MRI agent (FerroTrace, Ferronova). Mice with orthotopic LNCaP tumors underwent MRI 24 h after intravenous injection of nanoparticles. FAP and PSMA nanoparticles produced contrast enhancement on MRI when compared to control nanoparticles. FAP-targeted MRI increased the proportion of tumor contrast-enhancing black pixels by 13%, compared to PSMA. Analysis of changes in R2 values between healthy prostates and LNCaP tumors indicated an increase in contrast-enhancing pixels in the tumor border of 15% when targeting FAP, compared to PSMA. This study demonstrates the preclinical feasibility of PSMA and FAP-targeted MRI which can enable targeted image-guided focal therapy of localized prostate cancer.

Baseline gut microbiota composition is associated with oral mucositis and tumour recurrence in patients with head and neck cancer: a pilot study.

PURPOSE: Mounting evidence suggests that the gut microbiome influences radiotherapy efficacy and toxicity by modulating immune signalling. However, its contribution to radiotherapy outcomes in head and neck cancer (HNC) is yet to be investigated. This study, therefore, aimed to uncover associations between an individual's pre-therapy gut microbiota and (i) severity of radiotherapy-induced oral mucositis (OM), and (ii) recurrence risk in patients with HNC. METHODS: In this prospective pilot study, 20 patients with HNC scheduled to receive radiotherapy or chemoradiotherapy were recruited. Stool samples were collected before treatment and microbial composition was analysed using 16S rRNA gene sequencing. OM severity was assessed using the NCI-CTCAE scoring system. Patients were also followed for 12 months of treatment completion to assess tumour recurrence. RESULTS: Overall, 80% of the patients were male with a median age of 65.5 years. Fifty-three percent experienced mild/moderate OM while 47% developed severe OM. Furthermore, 18% experienced tumour relapse within 1 year of treatment completion. A pre-treatment microbiota enriched of Eubacterium, Victivallis, and Ruminococcus was associated with severe OM. Conversely, a higher relative abundance of immunomodulatory microbes Faecalibacterium, Prevotella, and Phascolarctobacterium was associated with a lower risk of tumour recurrence. CONCLUSION: Our results indicate that a patient's gut microbiota composition at the start of treatment is linked to OM severity and recurrence risk. We now seek to validate these findings to determine their ability to predict treatment outcomes in HNC, with the goal of using this data to inform second-generation microbial therapeutics to optimise treatment outcomes for patients with HNC.

Retrospective Cohort Study of Effects of the COVID-19 Pandemic on Tuberculosis Notifications, Vietnam, 2020.

We evaluated the effects of the coronavirus disease pandemic on diagnosis of and treatment for tuberculosis (TB) in Vietnam. We obtained quarterly notifications for TB and multidrug-resistant/rifampin-resistant (MDR/RR) TB from 2015-2020 and evaluated changes in monthly TB case notifications. We used an interrupted time series to assess the change in notifications and treatment outcomes. Overall, TB case notifications were 8% lower in 2020 than in 2019; MDR/RR TB notifications were 1% lower. TB case notifications decreased by 364 (95% CI -1,236 to 508) notifications per quarter and MDR/RR TB by 1 (95% CI -129 to 132) notification per quarter. The proportion of successful TB treatment outcomes decreased by 0.1% per quarter (95% CI -1.1% to 0.8%) in 2020 compared with previous years. Our study suggests that Vietnam was able to maintain its TB response in 2020, despite the pandemic.

P2Y1 agonist HIC in combination with androgen receptor inhibitor abiraterone acetate impairs cell growth of prostate cancer.

P2Y receptors belong to the large superfamily of G-protein-coupled receptors and play a crucial role in cell death and survival. P2Y1 receptor has been identified as a marker for prostate cancer (PCa). A previously unveiled selective P2Y1 receptor agonist, the indoline-derived HIC (1-(1-((2-hydroxy-5-nitrophenyl)(4-hydroxyphenyl)methyl)indoline-4-carbonitrile), induces a series of molecular and biological responses in PCa cells PC3 and DU145, but minimal toxicity to normal cells. Here, we evaluated the combinatorial effect of HIC with abiraterone acetate (AA) targeted on androgen receptor (AR) on the inhibition of PCa cells. Here, the presence of HIC and AA significantly inhibited cell proliferation of PC3 and DU145 cells with time-dependent manner as a synerfistic combination. Moreover, it was also shown that the anticancer and antimetastasis effects of the combinratorial drugs were noticed through a decrease in colony-forming ability, cell migration, and cell invasion. In addition, the HIC + AA induced apoptotic population of PCa cells as well as cell cycle arrest in G1 progression phase. In summary, these studies show that the combination of P2Y1 receptor agonist, HIC and AR inhibitor, AA, effectively improved the antitumor activity of each drug. Thus, the combinatorial model of HIC and AA should be a novel and promising therapeutic strategy for treating prostate cancer.

Effectiveness of Hyaluronic Acid Gel and Intrauterine Devices in Prevention of Intrauterine Adhesions after Hysteroscopic Adhesiolysis in Infertile Women.

STUDY OBJECTIVE: To compare the recurrence rate, post-treatment American Fertility Society (AFS) score, ongoing pregnancy rate, and endometrial thickness of 3 secondary prevention therapies in preventing recurrent intrauterine adhesions (IUAs) and increasing pregnancy rates in infertile women after hysteroscopic adhesiolysis. DESIGN: A retrospective study. SETTING: A private fertility hospital. PATIENTS: A total of 200 consecutive infertile women, with the desire to have a baby and were diagnosed as having IUAs detected by hysterosalpingogram, who underwent hysteroscopic adhesiolysis for IUAs from January, 2018 to May, 2020. INTERVENTIONS: Women who underwent hysteroscopic adhesiolysis received hormone therapy, and one of the 3 secondary preventions: hyaluronic acid (HA) gel alone, intrauterine devices (IUDs) alone, or HA gel + IUD. MEASUREMENTS AND MAIN RESULTS: Of the 200 women included in the final analysis, 121 received HA alone, 59 were treated with IUD alone, and 20 received HA gel + IUD combination. The mean post-treatment AFS score for IUAs was significantly lower in the HA gel + IUD group than the HA alone or the IUD alone groups (adjusted p = .01 and p = .02, respectively). Multivariable analysis revealed a significantly lower recurrence rate in the women after treatment with HA gel + IUD than HA alone (adjusted odds ratio, 0.19; 95% credible interval [CreI], 0.03-0.88). Women treated with HA gel + IUD also had reduced post-treatment AFS scores compared with HA alone (ß coefficients, -0.83; 95% CreI, -1.64 to -0.01). For ongoing pregnancy rates after in vitro fertilization, the adjusted odds ratio for HA gel + IUD vs HA alone was 2.03 (95% CreI, 0.44-11.00) and for IUD alone vs HA alone was 1.13 (95% CreI, 0.41-3.29), indicating nonsignificant differences. There were no differences observed in endometrial thickness on the day of embryo transfer among the 3 groups. CONCLUSION: The investigation of the primary outcome in reducing the recurrence rate IUA after treatment demonstrated that a combination of HA gel + IUD provides greater prevention of recurrent IUAs and may decrease post-treatment AFS scores for infertile women undergoing hysteroscopic adhesiolysis. However, for the secondary outcome of increasing pregnancy rates, there was no improvement in the ongoing pregnancy rates after in vitro fertilization.

Sensitive Electrochemical Non-Enzymatic Detection of Glucose Based on Wireless Data Transmission.

Miniaturization and wireless continuous glucose monitoring are key factors for the successful management of diabetes. Electrochemical sensors are very versatile and can be easily miniaturized for wireless glucose monitoring. The authors report a microneedle-based enzyme-free electrochemical wireless sensor for painless and continuous glucose monitoring. The microneedles (MNs) fabricated consist of a 3 × 5 sharp and stainless-steel electrode array configuration. Each MN in the 3 × 5 array has 575 µm × 150 µm in height and width, respectively. A glucose-catalyzing layer, porous platinum black, was electrochemically deposited on the tips of the MNs by applying a fixed cathodic current of 2.5 mA cm-2 for a period of 200 s. For the non-interference glucose sensing, the platinum (Pt)-black-coated MN was carefully packaged into a biocompatible ionomer, nafion. The surface morphologies of the bare and modified MNs were studied using field-emission scanning electron microscopy (FESEM) and energy-dispersive X-ray analysis (EDX). The wireless glucose sensor displayed a broad linear range of glucose (1→30 mM), a good sensitivity and higher detection limit of 145.33 µA mM-1 cm-2 and 480 µM, respectively, with bare AuMN as a counter electrode. However, the wireless device showed an improved sensitivity and enhanced detection limit of 445.75, 165.83 µA mM-1 cm-2 and 268 µM, respectively, with the Pt-black-modified MN as a counter electrode. The sensor also exhibited a very good response time (2 s) and a limited interference effect on the detection of glucose in the presence of other electroactive oxidizing species, indicating a very fast and interference-free chronoamperometric response.

What are the most effective community-based antimicrobial stewardship interventions in low- and middle-income countries? A narrative review.

Antimicrobial resistance (AMR) is a major global issue and antimicrobial stewardship is central to tackling its emergence. The burden of AMR disproportionately impacts low- and middle-income countries (LMICs), where capacity for surveillance and management of resistant pathogens is least developed. Poorly regulated antibiotic consumption in the community is a major driver of AMR, especially in LMICs, yet community-based interventions are neglected in stewardship research, which is often undertaken in high-income settings and/or in hospitals. We reviewed the evidence available to researchers and policymakers testing or implementing community-based antimicrobial stewardship strategies in LMICs. We critically appraise that evidence, deliver recommendations and identify outstanding areas of research need. We find that multifaceted, education-focused interventions are likely most effective in our setting. We also confirm that the quality and quantity of community-based stewardship intervention research is limited, with research on microbiological, clinical and economic sustainability most urgently needed.

AGITG MASTERPLAN: a randomised phase II study of modified FOLFIRINOX alone or in combination with stereotactic body radiotherapy for patients with high-risk and locally advanced pancreatic cancer.

BACKGROUND: Among patients with non-metastatic pancreatic cancer, 80% have high-risk, borderline resectable or locally advanced cancer, with a 5-year overall survival of 12%. MASTERPLAN evaluates the safety and activity of stereotactic body radiotherapy (SBRT) in addition to chemotherapy in these patients. METHODS AND DESIGN: MASTERPLAN is a multi-centre randomised phase II trial of 120 patients with histologically confirmed potentially operable pancreatic cancer (POPC) or inoperable pancreatic cancer (IPC). POPC includes patients with borderline resectable or high-risk tumours; IPC is defined as locally advanced or medically inoperable pancreatic cancer. Randomisation is 2:1 to chemotherapy + SBRT (investigational arm) or chemotherapy alone (control arm) by minimisation and stratified by patient cohort (POPC v IPC), planned induction chemotherapy and institution. Chemotherapy can have been commenced ≤28 days prior to randomisation. Both arms receive 6 × 2 weekly cycles of modified FOLFIRINOX (oxaliplatin (85 mg/m2 IV), irinotecan (150 mg/m2), 5-fluorouracil (2400 mg/m2 CIV), leucovorin (50 mg IV bolus)) plus SBRT in the investigational arm. Gemcitabine+nab-paclitaxel is permitted for patients unsuitable for mFOLFIRINOX. SBRT is 40Gy in five fractions with planning quality assurance to occur in real time. Following initial chemotherapy ± SBRT, resectability will be evaluated. For resected patients, adjuvant chemotherapy is six cycles of mFOLFIRINOX. Where gemcitabine+nab-paclitaxel was used initially, the adjuvant treatment is 12 weeks of gemcitabine and capecitabine or mFOLFIRINOX. Unresectable or medically inoperable patients with stable/responding disease will continue with a further six cycles of mFOLFIRINOX or three cycles of gemcitabine+nab-paclitaxel, whatever was used initially. The primary endpoint is 12-month locoregional control. Secondary endpoints are safety, surgical morbidity and mortality, radiological response rates, progression-free survival, pathological response rates, surgical resection rates, R0 resection rate, quality of life, deterioration-free survival and overall survival. Tertiary/correlative objectives are radiological measures of nutrition and sarcopenia, and serial tissue, blood and microbiome samples to be assessed for associations between clinical endpoints and potential predictive/prognostic biomarkers. Interim analysis will review rates of locoregional recurrence, distant failure and death after 40 patients complete 12 months follow-up. Fifteen Australian and New Zealand sites will recruit over a 4-year period, with minimum follow-up period of 12 months. DISCUSSION: MASTERPLAN evaluates SBRT in both resectable and unresectable patients with pancreatic ductal adenocarcinoma. TRIAL REGISTRATION: Australia New Zealand Clinical Trials Registry ACTRN12619000409178 , 13/03/2019. Protocol version: 2.0, 19 May 2019.