[Preliminary study on the role and mechanism of IL-6 receptor antagonists in improving post-infarction ventricular arrhythmia].

Objective: To investigate the effect of tocilizumab (TCZ) on ventricular arrhythmias (VAs) after myocardial infarction (MI) in Sprague-Dawley rats and explore its potential mechanism. Methods: The random number table method was used to divide 32 adult male Sprague-Dawley rats into 4 groups: Sham group, TCZ group, MI group and MI+TCZ group, with 8 rats in each group. The MI model was established by ligation of the left anterior descending branch of the coronary artery in the MI and MI+TCZ groups, and only sutured without ligation in the Sham and TCZ groups. TCZ was injected into the left superior cervical ganglion (SCG) of rats in the TCZ and MI+TCZ groups after successful modeling or sham operation, and the same amount of normal saline was injected in the Sham and MI groups. 24 h after successful modeling, ECG of rats in each group was recorded, heart rate variability (HRV, including low frequency power (LF), high frequency power (HF), LF/HF ratio), QT interval, QTc interval were calculated, and left ventricular effective refractory period (ERP) and VA inducibility were measured. Myocardial infarct size and tissue changes were observed with triphenyl tetrazolium chloride staining and HE staining. Real-time PCR analysis was used to detect the messager RNA (mRNA) expression of interleukin-6 (IL-6) and signal transducer and activator of transcription (STAT) 3 in SCG and potassium voltage-gated channel subfamily D member 2 (Kcnd2) in myocardial infarction periphery. The expression of c-fos in SCG was detected by immunofluorescence staining. Results: Compared with Sham group and MI+TCZ group, rats in MI group had higher LF and LF/HF ratio, longer QT interval and QTc interval, more VAs induced, lower HF and shorter ERP (P all<0.05). Triphenyl tetrazolium chloride staining and HE staining showed that rats in the Sham and TCZ groups had normal myocardial tissue structure, those in the MI group had severe myocardial injury, and those in the MI+TCZ group had less myocardial injury than those in the MI group. Real-ime PCR analysis showed that compared with Sham group and MI+TCZ group, mRNA expression levels of IL-6 and STAT3 in SCG of rats in MI group were higher, and mRNA expression level of myocardial Kcnd2 was lower (P all<0.05). Immunofluorescence staining showed that the content of c-fos in SCG of rats in MI group was higher than that of Sham group and MI+TCZ group (P all<0.05). Conclusions: TCZ may reduce neural activity of the SCG after MI by inhibiting the IL-6/STAT3 signaling pathway, thereby alleviating myocardial injury and inhibiting VAs.

Parental use and acceptance of an accessible, commercially available intraoral camera for teledentistry in their children.

PURPOSE: The potential of combining teledentistry and engaging parents as underutilised resources to monitor paediatric dental health was emphasised during the COVID-19 pandemic and remains underexplored. This study aims to assess parental acceptance and use of a commercially available intraoral camera (IOC) for effective remote monitoring. METHODS: 47 child-parent dyads, where the parent was the main caregiver and the child was treated under general anaesthesia for early childhood caries, were recruited. Caregivers were trained to image their child's teeth on a commercially available IOC. Subsequently, submitted images were reviewed asynchronously by dentists for image quality, presence of dislodged fillings, abscesses, cavitation, and oral hygiene. Post-surgery monitoring was performed using teledentistry at 1 and 2 months and in-person at 4 months. A modified Telehealth Usability Questionnaire (TUQ) was used to record caregiver acceptance for study procedures. RESULTS: A mean TUQ of 6.09 out of 7 was scored by caregivers. Caregiver-reported issues were limited to problems with technique and child uncooperativeness. The number of clear images during the second teledentistry review was improved compared to the first (p = 0.007). 68% of children liked having images of their teeth taken. CONCLUSION: This study supports the feasibility of using an IOC as a clinically appropriate avenue for teledentistry with a high level of caregiver-child acceptance.

The correlation between Helicobacter pylori infection and iron deficiency anemia in women.

OBJECTIVE: In recent years, Helicobacter pylori (H. pylori) has been increasingly associated with extra-digestive manifestations, including scleroderma, rheumatism, and blood system diseases. Iron deficiency anemia (IDA) is a common chronic disease worldwide, with an insidious onset, but as the disease progresses, it will eventually seriously affect the quality of life of patients. The aim of our study was to investigate the relationship between H. pylori infection, iron deficiency (ID), and IDA, and to identify potential serological markers. PATIENTS AND METHODS: We conducted a cross-sectional study of 998 individuals who had regular physical examinations at Beijing Shijitan Hospital from January 2021 to March 2022. We detected H. pylori infection by the 13C breath test, and recorded the patient's serum iron, ferritin, transferrin saturation, blood count, etc. We assessed the association between IDA and H. pylori infection and related serum markers using logistic regression and multiple linear regression. Afterward, we analyzed the correlation between sex and potential serum biomarkers. RESULTS: Among all study participants, 57.5% of patients had H. pylori and 42.5% did not have H. pylori. ID and IDA were significantly associated with H. pylori infection in women (p=0.031). This association persisted after further adjustment for sex, metabolic variables, liver function, and kidney function. Fasting blood glucose, triglycerides, and uric acid may be associated with IDA. CONCLUSIONS: In women, H. pylori infection is associated with ID and IDA. The relationship between H. pylori and IDA may be mediated by glycometabolism, lipid metabolism, and uric acid metabolism.

The current state of understanding of oncology expanded access programs in Malaysia.

INTRODUCTION: An expanded access program (EAP) is a regulatory mechanism that provides access to an investigational drug, which is not approved for use, in treating life-threatening conditions when all the standard-ofcare treatments are exhausted. MATERIALS AND METHODS: An online, anonymous, voluntary survey was conducted to assess the level of knowledge and understanding about EAPs among Malaysian oncologists using SurveyMonkey® between April 2020 and June 2020. Oncologists who had enquired about EAP in the past, were invited at random to participate in the survey. Participants who did not provide consent or failed to complete the survey were excluded. RESULTS: A total of 15 oncologists participated in the survey, from both public (46.6%) and private (46.6%) practices. Most respondents (80%) had filed between 1 to 10 EAP applications in the past 12 months. For 73.3% respondents, resources or training were not provided for EAPs from institutions. Around 53% of the respondents reported that their knowledge of EAPs and application processes including country regulations is 'good'. The majority of respondents (73.3%) reported that the educational modules on an overview of EAPs, country regulations and the EAP application process will be beneficial. Most participants received information about the existing EAPs either by reaching out to a pharmaceutical sponsor or through another health care provider and some received information about the existing EAPs through their institutions or patients/caregivers. Most of the respondents recommended that pharmaceutical companies should have readily available information related to the availability and application of EAPs for all pipeline products on their websites. DISCUSSION: EAPs are crucial treatment access pathways to provide investigational drugs to patients who have exhausted their treatment options and are not eligible for participation in clinical trials. Malaysian oncologists have a fair understanding about the EAPs and the application processes. CONCLUSION: Additional training and awareness are needed for Malaysian oncologists to upscale the utilisation of EAPs.

Suction rectal biopsy (SRB) in Hirschsprung's Disease: Is a single macroscopically adequate sample sufficient?

Hirschsprung's Disease (HD) is a congenital disorder causing severe constipation in infants and children. Suction rectal biopsy (SRB) is the preferred technique for obtaining tissue samples for histopathological evaluation. In low-resource settings like Malaysia, cost-effective diagnostic approaches are necessary, making single sample SRB valuable. This study evaluates the diagnostic accuracy and sufficiency of a single macroscopically adequate sample in suction rectal biopsies for the histopathological confirmation of HD. We conducted a retrospective study of children who underwent suction rectal biopsies for the diagnosis of HD at Hospital Raja Perempuan Zainab II (HRPZII), Kota Bharu, Kelantan. A total of 68 patients were included in the study. The inadequacy rate for bedside SRB was 14%, comparable to current literature. Our study found no statistically significant association between sample inadequacy and gestational age, gender, birth weight, or weight at biopsy. Complication rates were 0%, consistent with literature reports. Calretinin staining, an additional technique, was performed in 23 biopsy episodes, with a 4.3% inadequacy rate, compared to 20% in specimens not subjected to calretinin staining. The cost of SRB almost doubled with each additional sample taken, significant in low-resource environments. In conclusion, single sample SRBs can be adequately diagnostic and cost-effective in low-resource settings, providing valuable insights for healthcare facilities in Malaysia and other developing countries. The use of adjunctive techniques such as calretinin staining may improve diagnostic accuracy while maintaining cost-effectiveness. Further prospective studies with larger sample sizes are needed to validate these findings.

Diagnosis and management of Barrett esophagus: European Society of Gastrointestinal Endoscopy (ESGE) Guideline.

MR1 : ESGE recommends the following standards for Barrett esophagus (BE) surveillance:- a minimum of 1-minute inspection time per cm of BE length during a surveillance endoscopy- photodocumentation of landmarks, the BE segment including one picture per cm of BE length, and the esophagogastric junction in retroflexed position, and any visible lesions- use of the Prague and (for visible lesions) Paris classification- collection of biopsies from all visible abnormalities (if present), followed by random four-quadrant biopsies for every 2-cm BE length.Strong recommendation, weak quality of evidence. MR2: ESGE suggests varying surveillance intervals for different BE lengths. For BE with a maximum extent of ≥ 1 cm and < 3 cm, BE surveillance should be repeated every 5 years. For BE with a maximum extent of ≥ 3 cm and < 10 cm, the interval for endoscopic surveillance should be 3 years. Patients with BE with a maximum extent of ≥ 10 cm should be referred to a BE expert center for surveillance endoscopies. For patients with an irregular Z-line/columnar-lined esophagus of < 1 cm, no routine biopsies or endoscopic surveillance are advised.Weak recommendation, low quality of evidence. MR3: ESGE suggests that, if a patient has reached 75 years of age at the time of the last surveillance endoscopy and/or the patient's life expectancy is less than 5 years, the discontinuation of further surveillance endoscopies can be considered. Weak recommendation, very low quality of evidence. MR4: ESGE recommends offering endoscopic eradication therapy using ablation to patients with BE and low grade dysplasia (LGD) on at least two separate endoscopies, both confirmed by a second experienced pathologist.Strong recommendation, high level of evidence. MR5: ESGE recommends endoscopic ablation treatment for BE with confirmed high grade dysplasia (HGD) without visible lesions, to prevent progression to invasive cancer.Strong recommendation, high level of evidence. MR6: ESGE recommends offering complete eradication of all remaining Barrett epithelium by ablation after endoscopic resection of visible abnormalities containing any degree of dysplasia or esophageal adenocarcinoma (EAC).Strong recommendation, moderate quality of evidence. MR7: ESGE recommends endoscopic resection as curative treatment for T1a Barrett's cancer with well/moderate differentiation and no signs of lymphovascular invasion.Strong recommendation, high level of evidence. MR8: ESGE suggests that low risk submucosal (T1b) EAC (i. e. submucosal invasion depth ≤ 500 µm AND no [lympho]vascular invasion AND no poor tumor differentiation) can be treated by endoscopic resection, provided that adequate follow-up with gastroscopy, endoscopic ultrasound (EUS), and computed tomography (CT)/positrion emission tomography-computed tomography (PET-CT) is performed in expert centers.Weak recommendation, low quality of evidence. MR9: ESGE suggests that submucosal (T1b) esophageal adenocarcinoma with deep submucosal invasion (tumor invasion > 500 µm into the submucosa), and/or (lympho)vascular invasion, and/or a poor tumor differentiation should be considered high risk. Complete staging and consideration of additional treatments (chemotherapy and/or radiotherapy and/or surgery) or strict endoscopic follow-up should be undertaken on an individual basis in a multidisciplinary discussion.Strong recommendation, low quality of evidence. MR10 A: ESGE recommends that the first endoscopic follow-up after successful endoscopic eradication therapy (EET) of BE is performed in an expert center.Strong recommendation, very low quality of evidence. B: ESGE recommends careful inspection of the neo-squamocolumnar junction and neo-squamous epithelium with high definition white-light endoscopy and virtual chromoendoscopy during post-EET surveillance, to detect recurrent dysplasia.Strong recommendation, very low level of evidence. C: ESGE recommends against routine four-quadrant biopsies of neo-squamous epithelium after successful EET of BE.Strong recommendation, low level of evidence. D: ESGE suggests, after successful EET, obtaining four-quadrant random biopsies just distal to a normal-appearing neo-squamocolumnar junction to detect dysplasia in the absence of visible lesions.Weak recommendation, low level of evidence. E: ESGE recommends targeted biopsies are obtained where there is a suspicion of recurrent BE in the tubular esophagus, or where there are visible lesions suspicious for dysplasia.Strong recommendation, very low level of evidence. MR11: After successful EET, ESGE recommends the following surveillance intervals:- For patients with a baseline diagnosis of HGD or EAC:at 1, 2, 3, 4, 5, 7, and 10 years after last treatment, after which surveillance may be stopped.- For patients with a baseline diagnosis of LGD:at 1, 3, and 5 years after last treatment, after which surveillance may be stopped.Strong recommendation, low quality of evidence.

[A case of metastatic breast cancer complicated by pulmonary tumor thrombotic microangiopathy].

Pulmonary tumor thrombotic microangiopathy is a malignancy-related complication with rapid progression and high mortality. To improve the understanding of the disease, early diagnosis and treatment are key to successful treatment. A 39-year-old patient with pulmonary hypertension transferred from another hospital was admitted to the First Affiliated Hospital of Guangzhou Medical University on September 26, 2021. The patient developed shortness of breath and progressive exacerbation over the past month. No pulmonary artery embolism was seen on computed tomography pulmonary angiography (CTPA) at the outside hospital where the breast cancer was diagnosed. Pulmonary tumor thrombotic microangiopathy was immediately considered on admission and oncological endocrine therapy was started. After treatment, the patient's dyspnoea improved, PET-CT showed significant tumor regression, and cardiac ultrasound showed a significant decrease in pulmonary artery pressure. The successful treatment experience of this case was summarized for reference.

The impact of lymph node ratio on disease recurrence in papillary thyroid microcarcinoma.

INTRODUCTION: Lymph node (LN) metastases in papillary thyroid microcarcinomas (microPTCs) are common. The lymph node ratio (LNR) has been proposed as a risk factor for recurrence in papillary thyroid cancer. However, its relevance in microPTC is undetermined. METHODS: Patients who underwent resection of their microPTC with concomitant LN clearance between 2005 and 2018 were identified. The LNR was calculated as the ratio of positive LNs to the total number of LNs. RESULTS: Data on 50 patients (36 female [72%]; median age 47 years [range: 19-84]) who underwent LN clearance (28 central [56%] vs 22 central + lateral [44%]) were analysed. Positive LNs were found in over two-thirds of the patients (n = 34; 68%). After a median follow-up of 61 months, 14 patients (28%) had developed recurrence. Positive LNs were not found to impact recurrence-free survival; extranodal extension and an LNR ≥ 0.26 were found to significantly increase the risk of recurrence on unadjusted analyses (p < 0.05). CONCLUSIONS: LN metastases are frequent among patients with microPTC. A higher LNR seems to be associated with recurrence. Additional studies are needed to further clarify these findings and to assess the possible role of LNR in treatment and surveillance.

Adequacy of endoscopic recognition and surveillance of gastric intestinal metaplasia and atrophic gastritis: A multicentre retrospective study in low incidence countries.

BACKGROUND: Gastric atrophy (GA) and gastric intestinal metaplasia (GIM) are precursor conditions to gastric adenocarcinoma (GAC) and should be monitored endoscopically in selected individuals. However, little is known about adherence to recommendations in clinical practice in low-risk countries. OBJECTIVE: The aim of this study was to evaluate endoscopic recognition and adequacy of surveillance for GA and GIM in countries with low GAC prevalence. METHODS: We retrospectively analysed patients diagnosed with GIM or GA in three centers in The Netherlands and UK between 2012 and 2019. Cases with GIM and/or GA diagnosis at index endoscopy were retrieved through systematic search of pathology databases using 'gastric' and 'intestinal metaplasia' or 'atrophy' keywords. Endoscopy reports were analysed to ascertain accuracy of endoscopic diagnoses. Adequacy of surveillance was assessed following histological diagnosis at the index endoscopy based on ESGE guidelines published in 2012. RESULTS: We included 396 patients with a median follow-up of 57.2 months. Mean age was 66 years and the rates of antrum-predominant versus extensive GIM were comparable (37% vs 38%). Endoscopic recognition rates were 48.5% for GA and 16.3% for GIM. Surveillance was adequately carried out in 215 of 396 patients (54.3%). CONCLUSION: In countries with a low incidence of GAC, the rate of endoscopic recognition of gastric pre-cancerous lesions and adherence to surveillance recommendation are low. Substantial improvement is required in endoscopic training and awareness of guidelines recommendation in order to optimise detection and management of pre-malignant gastric conditions.

Anatomical tilt lateral wrist X-ray - Not always 22°.

INTRODUCTION: Open Reduction and Internal Fixation (ORIF) with volar locking plates are commonly used to manage distal radial fractures. The anatomical tilt lateral (ATL) wrist X-ray is often required for evaluation of intra-articular screw penetration due to the screw position. This study aims to evaluate the correlation between the tube angulation given by performing radiographers for the ATL projection and the post-examination measurement of radial inclination (RI) on the Posterior Anterior (PA) wrist image. METHODS: A retrospective review was performed for 36 patients. A standardised method developed by Kreder et al. (1996) was used to measure the RI on the PA wrist image. All ATL images sent into Picture Archiving and Communications System (PACS) have the tube angulation applied annotated on the image. Pearson's correlation was used to analyse the co-relationship between the RI and the tube angle applied for ATL projection. RESULTS: The average angle of RI measured by the four observers was 19. Normality of 0.385 was established. A positive correlation (p = 0.792) between the RI and the tube angle applied for ATL was found. CONCLUSION: Our study found a strong positive correlation between the tube angulation applied by performing radiographers for the ATL projection and the post-examination RI measured on the PA wrist image by the independent reviewers. This suggests that radiographers can use the measured RI to apply the tube angulation when performing the ATL wrist X-ray, instead of estimating the tube angulation to be applied. IMPLICATIONS FOR PRACTICE: Using the measured RI to apply the tube angulation when performing the ATL wrist X-ray will ensure a more reliable and reproducible way that could reduce the number of repeated images and, thus, unnecessary radiation dose to patients.

Reference values for six-minute walk distance and six-minute walk work in Caucasian adults.

RATIONALE: The six-minute walk test (6MWT) is a practical and simple field-based test to assess physical capacity. Several reference equations for six-minute walking distance (6MWD, m) exist, but have a number of limitations that decrease their clinical utility. In addition, no reference equations exist for the 6MWT-derived outcome six-minute walk work (6MWORK, kg.m). OBJECTIVES: To establish new reference equations for 6MWD and 6MWORK on a 20 m course using data from the population-based Canadian Cohort Obstructive Lung Disease study. METHODS AND MEASUREMENTS: A total of 335 participants without obstructive or restrictive pulmonary function, with normal self-reported health status, normal exercise capacity, and <30 pack years cigarette smoking history were selected to create a representative sample of Canadian adults aged ≥40 years. All participants performed two 6MWTs. Reference equations were derived using multiple regression analyses. MAIN RESULTS: On average, 6MWD and 6MWORK were 541±98 m and 41.3 ± 11.2 kg.m, respectively. All outcomes were significantly greater in males than females. Sex-specific reference equations were derived from the results of 6MWD and 6MWORK with an explained variance of 24 to 35%. CONCLUSIONS: This study established reference equations for 6MWD and 6MWORK on a 20 m course in Caucasian males and females aged ≥40 years with normal pulmonary function, self-reported health status and exercise capacity. These newly derived reference equations add value to the assessment of functional capacity in clinical practice.

[Associations of genetic variations in pyroptosis related genes with acute adverse events in postoperative rectal cancer patients receiving concurrent chemoradiotherapy].

Objective: This study aims to investigate the associations between genetic variations of pyroptosis pathway related key genes and adverse events (AEs) of postoperative chemoradiotherapy (CRT) in patients with rectal cancer. Methods: DNA was extracted from the peripheral blood which was collected from 347 patients before CRT. Sequenom MassARRAY was used to detect the genotypes of 43 haplotype-tagging single nucleotide polymorphisms (htSNPs) in eight pyroptosis genes, including absent in melanoma 2 (AIM2), caspase-1 (CASP1), caspase-4(CASP4), caspase-5 (CASP5), caspase-11 (CASP11), gasdermin D (GSDMD), gasdermin E (GSDME) and NLR family pyrin domain containing 3 (NLRP3). The associations between 43 htSNPs and AEs were evaluated by the odd ratios (ORs) and 95% confidence intervals (CIs) by unconditional logistic regression models, adjusted for sex, age, clinical stage, tumor grade, Karnofsky performance status (KPS), surgical procedure, and tumor location. Results: Among the 347 patients with rectal cancer underwent concurrent CRT with capecitabine after surgery, a total of 101(29.1%) occurred grade ≥ 2 leukopenia. rs11226565 (OR=0.41, 95% CI: 0.21-0.79, P=0.008), rs579408(OR=1.54, 95% CI: 1.03-2.29, P=0.034) and rs543923 (OR=0.63, 95% CI: 0.41-0.98, P=0.040) were significantly associated with the occurrence of grade ≥ 2 leukopenia. One hundred and fifty-six (45.0%) had grade ≥ 2 diarrhea, two SNPs were significantly associated with the occurrence of grade ≥ diarrhea, including CASP11 rs10880868 (OR=0.55, 95% CI: 0.33-0.91, P=0.020) and GSDME rs2954558 (OR=1.52, 95% CI: 1.01-2.31, P=0.050). In addition, sixty-six cases (19.0%) developed grade ≥2 dermatitis, three SNPs that significantly associated with the risk of grade ≥2 dermatitis included GSDME rs2237314 (OR=0.36, 95% CI: 0.16-0.83, P=0.017), GSDME rs12540919 (OR=0.52, 95% CI: 0.27-0.99, P=0.045) and NLRP3 rs3806268 (OR=1.51, 95% CI: 1.03-2.22, P=0.037). There was no significant difference in the association between other genetic variations and AEs of rectal cancer patients (all P>0.05). Surgical procedure and tumor location had great impacts on the occurrence of grade ≥2 diarrhea and dermatitis (all P<0.01). Conclusion: The genetic variants of CASP4, CASP11, GSDME and NLRP3 are associated with the occurrence of AEs in patients with rectal cancer who received postoperative CRT, suggesting they may be potential genetic markers in predicting the grade of AEs to achieve individualized treatment of rectal cancer.

Sweet's syndrome: A review from two tertiary hospitals in Malaysia.

INTRODUCTION: Sweet's syndrome (SS) also known as acute febrile neutrophilic dermatosis, is an uncommon disease characterised by acute onset of tender, violaceous or erythematous, oedematous papules, nodules or plaques, with fever. It is classified into classic, malignancyassociated, and drug-induced subtypes.The aims of this study is to evaluate the subtypes, clinical features, laboratory profiles, and treatment of patients with SS. MATERIALS AND METHODS: We did a retrospective medical record review of all patients with SS from July 2014 to July 2018 at Hospital Queen Elizabeth and Hospital Pulau Pinang, both tertiary hospitals in Malaysia. RESULTS: Twenty-nine patients were included. Approximately half of the patients (15) were females with a mean age of onset of 50.93 (± 11.52) years. The most common subtype was classic (62.0%) followed by malignancy-associated (31.0%) and drug-induced (6.9%). Among the patients with the classic subtype, infective-related causes (50.0%) were the most common. Among the patients with malignancy, eight had haematological malignancy and one had a solid tumour. Two-third of the malignancies were diagnosed within a year after the diagnosis of SS. Eight of our patients in Sabah had mycobacterial infections with three having concomitant haematological malignancies. Patients with malignancy-associated SS had lower mean haemoglobin (p=0.018) and mean platelet count (p=0.031). Itch was associated with the presence of pustules (p=0.038). Histopathological examination of all skin lesions showed dermal neutrophilic infiltrates and 25 (86.2%) of them had papillary dermal oedema. The study was limited by its retrospective design. The sample size was small likely due to the uncommon occurrence of this condition. CONCLUSION: SS is an uncommon dermatosis with distinctive clinical and histopathological features. Screening for underlying malignancy is essential especially for those who present with anaemia, thrombocytopenia, and pathergy phenomenon. Mycobacterial infection should be considered in this region due to high tuberculosis burden.

Augmenting control arms with real-world data for cancer trials: Hybrid control arm methods and considerations.

Background: Hybrid controlled trials with real-world data (RWD), where the control arm is composed of both trial and real-world patients, could facilitate research when the feasibility of randomized controlled trials (RCTs) is challenging and single-arm trials would provide insufficient information. Methods: We propose a frequentist two-step borrowing method to construct hybrid control arms. We use parameters informed by a completed randomized trial in metastatic triple-negative breast cancer to simulate the operating characteristics of dynamic and static borrowing methods, highlighting key trade-offs and analytic decisions in the design of hybrid studies. Results: Simulated data were generated under varying residual-bias assumptions (no bias: HRRWD = 1) and experimental treatment effects (target trial scenario: HRExp = 0.78). Under the target scenario with no residual bias, all borrowing methods achieved the desired 88% power, an improvement over the reference model (74% power) that does not borrow information externally. The effective number of external events tended to decrease with higher bias between RWD and RCT (i.e. HRRWD away from 1), and with weaker experimental treatment effects (i.e. HRExp closer to 1). All dynamic borrowing methods illustrated (but not the static power prior) cap the maximum Type 1 error over the residual-bias range considered. Our two-step model achieved comparable results for power, type 1 error, and effective number of external events borrowed compared to other borrowing methodologies. Conclusion: By pairing high-quality external data with rigorous simulations, researchers have the potential to design hybrid controlled trials that better meet the needs of patients and drug development.

Quantification of TFF3 expression from a non-endoscopic device predicts clinically relevant Barrett's oesophagus by machine learning.

BACKGROUND: Intestinal metaplasia (IM) is pre-neoplastic with variable cancer risk. Cytosponge-TFF3 test can detect IM. We aimed to 1) assess whether quantitative TFF3 scores can distinguish clinically relevant Barrett's oesophagus (BO) (C≥1 or M≥3) from focal IM pathologies (C<1, M<3 or IM of gastro-oesophageal junction); 2) whether TFF3 counts can be automated to inform clinical practice. METHODS: Patients from the Barett's oEsophagus Screening Trial 2 (BEST2) case-control and BEST3 randomised trials were used. For aim 1, TFF3-positive glands were scored manually and correlated with clinical diagnosis. For aim 2, machine learning approach was used to obtain TFF3 count and logistic regression with cross-validation was trained on the BEST2 dataset (n = 529) and tested in the BEST3 dataset (n = 158). FINDINGS: Patients with clinically relevant BO had higher mean TFF3 gland count compared to focal IM pathologies (mean difference 4.14; 95% confidence interval, CI 2.76-5.52, p < 0.001). The mean class-balanced validation accuracy was 0.84 (95% CI 0.77-0.90), and precision of 0.95 (95% CI 0.87-1.00) for detecting clinically relevant BO. Applying this model on BEST3 showed precision of 0.91 (95% CI 0.85-0.97) for focal IM pathologies with a class-balanced accuracy of 0.77 (95% CI 0.69-0.84). Using this model, 55% of patients (87/158) in BEST3 would fall below the threshold for clinically relevant BO and could avoid gastroscopy, while only missing 5.1% of patients (8/158). INTERPRETATION: Automated Cytosponge-TFF3 gland quantification may enable thresholds to be set to trigger confirmatory gastroscopy to minimize overdiagnosis of focal IM pathologies with very low cancer-associated risk. FUNDING: Cancer Research UK (12088/16893 and C14478/A21047).

Barrett's Oesophagus: Today's Mistake and Tomorrow's Wisdom in Screening and Prevention.

Background: Oesophageal adenocarcinoma (OAC) is a lethal cancer with an overall 5-year survival of <20%. Given the presence of a pre-invasive disease stage, also known as Barrett's oesophagus (BO), and the availability of minimally invasive treatments for BO-related neoplasia, it is thought that early detection is the best strategy to improve patient outcomes. Clinical guidelines recommend endoscopic screening in patients with symptoms of acid reflux and additional risk factors. This strategy is flawed by the cost and invasiveness of endoscopy as well as by the fact that a significant proportion of OAC patients deny a history of reflux symptoms. Summary: New research on the use of epidemiologic and clinical data has allowed the creation of risk-prediction algorithms to identify the population at risk. In addition, newer less-invasive devices such as transnasal endoscopy, Cytosponge, volumetric laser endomicroscopy, and volatile organic compounds are emerging as promising options to allow screening in the primary care setting. Finally, there is an opportunity to intervene at the pre-invasive stage with pharmacological strategies to reduce the risk burden. Key Messages: In this review, we provide a critical appraisal of the different screening approaches and chemopreventive strategies and a guide to readers on how to implement research evidence in clinical practice.