Hong Kong consensus recommendations on the management of pancreatic ductal adenocarcinoma.

This project was undertaken to develop the first set of consensus statements regarding the management of pancreatic ductal adenocarcinoma (PDAC) in Hong Kong, with the goal of providing guidance to local clinicians. A multidisciplinary panel of experts discussed issues surrounding current PDAC management and reviewed evidence gathered in the local context to propose treatment recommendations. The experts used the Delphi approach to finalise management recommendations. Consensus was defined as ≥80% acceptance among all expert panel members. Thirty-nine consensus statements were established. These statements cover all aspects of PDAC management, including diagnosis, resectability criteria, treatment modalities according to resectability, personalised management based on molecular profiling, palliative care, and supportive care. This project fulfils the need for guidance regarding PDAC management in Hong Kong. To assist clinicians with treatment decisions based on varying levels of evidence and clinical experience, treatment options are listed in several consensus statements.

Efficacy and safety of ocrelizumab in patients with relapsing multiple sclerosis: Real-world experience of two Swiss multiple sclerosis centers.

BACKGROUND: Ocrelizumab (OCR) is a humanized monoclonal antibody directed against CD-20 positive lymphocytes, mainly B-lymphocytes. OCR is approved for treatment of primary progressive (PPMS) and relapsing multiple sclerosis (RMS). This study aims to provide real-world safety and efficacy data of people with RMS treated with OCR in two Swiss Multiple Sclerosis (MS) centers. METHODS: We have conducted a retrospective data analysis using the patient cohorts from the Cantonal Hospital Aarau and Bern University Hospital (RMS: n = 235). Statistical analyses were performed with Mann-Whitney U-Test, Chi-squared test and Spearman-Rho-Correlation. Adjustment for multiple testing was performed by Bonferroni procedure. RESULTS: After initiation of OCR, there was a decrease in disease activity in RMS patients. In our study, 152/190 (80.0 %) RMS patients fulfilled the criteria for NEDA-3 12 months and 88/104 (84.6 %) showed NEDA-3 24 months after OCR initiation. The most frequent adverse events (AEs) in our study were infections, taking place in 78/235 (33.2 %) RMS patients. COVID-19 was the most common infection, followed by urinary infections and other respiratory infections and infectious adverse events occurred significantly more frequent in patients with reduced IgG serum concentration. CONCLUSIONS: Our real-world study showed OCR being associated with low rates of any type of MS disease activity as indicated by NEDA-3. The adverse event profile is comparable to the known events especially infections and an association between infections and reduced IgG serum concentration was found.

Stevens-Johnson syndrome and toxic epidermal necrolysis in Hong Kong.

INTRODUCTION: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) [hereafter, SJS/TEN] are uncommon but severe mucocutaneous reactions. Although they have been described in many populations worldwide, data from Hong Kong are limited. Here, we explored the epidemiology, disease characteristics, aetiology, morbidity, and mortality of SJS/TEN in Hong Kong. METHODS: This retrospective cohort study included all hospitalised patients who had been diagnosed with SJS/TEN in Prince of Wales Hospital from 1 January 2004 to 31 December 2020. RESULTS: There were 125 cases of SJS/TEN during the 17-year study period. The annual incidence was 5.07 cases per million. The mean age at onset was 51.4 years. The mean maximal body surface area of epidermal detachment was 23%. Overall, patients in 32% of cases required burns unit or intensive care unit admission. Half of the cases involved concomitant sepsis, and 23.2% of cases resulted in multiorgan failure or disseminated intravascular coagulation. The mean length of stay was 23.9 days. The cause of SJS/TEN was attributed to a drug in 91.9% of cases, including 84.2% that involved anticonvulsants, allopurinol, antibiotics, or analgesics. In most cases, patients received treatment comprising either best supportive care alone (35.2%) or combined with intravenous immunoglobulin (43.2%). The in-hospital mortality rate was 21.6%. Major causes of death were multiorgan failure and/or fulminant sepsis (81.5%). CONCLUSION: This study showed that SJS/TEN are uncommon in Hong Kong but can cause substantial morbidity and mortality. Early recognition, prompt withdrawal of offending agents, and multidisciplinary supportive management are essential for improving clinical outcomes.

Genome-wide association studies and Mendelian randomization analyses provide insights into the causes of early-onset colorectal cancer.

BACKGROUND: The incidence of early-onset colorectal cancer (EOCRC; diagnosed <50 years of age) is rising globally; however, the causes underlying this trend are largely unknown. CRC has strong genetic and environmental determinants, yet common genetic variants and causal modifiable risk factors underlying EOCRC are unknown. We conducted the first EOCRC-specific genome-wide association study (GWAS) and Mendelian randomization (MR) analyses to explore germline genetic and causal modifiable risk factors associated with EOCRC. PATIENTS AND METHODS: We conducted a GWAS meta-analysis of 6176 EOCRC cases and 65 829 controls from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colorectal Transdisciplinary Study (CORECT), the Colon Cancer Family Registry (CCFR), and the UK Biobank. We then used the EOCRC GWAS to investigate 28 modifiable risk factors using two-sample MR. RESULTS: We found two novel risk loci for EOCRC at 1p34.1 and 4p15.33, which were not previously associated with CRC risk. We identified a deleterious coding variant (rs36053993, G396D) at polyposis-associated DNA repair gene MUTYH (odds ratio 1.80, 95% confidence interval 1.47-2.22) but show that most of the common genetic susceptibility was from noncoding signals enriched in epigenetic markers present in gastrointestinal tract cells. We identified new EOCRC-susceptibility genes, and in addition to pathways such as transforming growth factor (TGF) ß, suppressor of Mothers Against Decapentaplegic (SMAD), bone morphogenetic protein (BMP) and phosphatidylinositol kinase (PI3K) signaling, our study highlights a role for insulin signaling and immune/infection-related pathways in EOCRC. In our MR analyses, we found novel evidence of probable causal associations for higher levels of body size and metabolic factors-such as body fat percentage, waist circumference, waist-to-hip ratio, basal metabolic rate, and fasting insulin-higher alcohol drinking, and lower education attainment with increased EOCRC risk. CONCLUSIONS: Our novel findings indicate inherited susceptibility to EOCRC and suggest modifiable lifestyle and metabolic targets that could also be used to risk-stratify individuals for personalized screening strategies or other interventions.

2023 updated MASCC/ESMO consensus recommendations: prevention of nausea and vomiting following high-emetic-risk antineoplastic agents.

PURPOSE: This systematic review updates the MASCC/ESMO recommendations for high-emetic-risk chemotherapy (HEC) published in 2016-2017. HEC still includes cisplatin, carmustine, dacarbazine, mechlorethamine, streptozocin, and cyclophosphamide in doses of > 1500 mg/m2 and the combination of cyclophosphamide and an anthracycline (AC) in women with breast cancer. METHODS: A systematic review report following the PRISMA guidelines of the literature from January 1, 2015, until February 1, 2023, was performed. PubMed (Ovid), Scopus (Google), and the Cochrane Database of Systematic Reviews were searched. The literature search was limited to randomized controlled trials, systematic reviews, and meta-analyses. RESULTS: Forty-six new references were determined to be relevant. The main topics identified were (1) steroid-sparing regimens, (2) olanzapine-containing regimens, and (3) other issues such as comparisons of antiemetics of the same drug class, intravenous NK1 receptor antagonists, and potentially new antiemetics. Five updated recommendations are presented. CONCLUSION: There is no need to prescribe steroids (dexamethasone) beyond day 1 after AC HEC, whereas a 4-day regimen is recommended in non-AC HEC. Olanzapine is now recommended as a fixed part of a four-drug prophylactic antiemetic regimen in both non-AC and AC HEC. No major differences between 5-HT3 receptor antagonists or between NK1 receptor antagonists were identified. No new antiemetic agents qualified for inclusion in the updated recommendations.

Monitoring environmental microbiomes: Alignment of microbiology and computational biology competencies within a culturally integrated curriculum and research framework.

We have developed a flexible undergraduate curriculum that leverages the place-based research of environmental microbiomes to increase the number of Indigenous researchers in microbiology, data science and scientific computing. Monitoring Environmental Microbiomes (MEM) provides a curriculum and research framework designed to integrate an Indigenous approach when conducting authentic scientific research and to build interest and confidence at the undergraduate level. MEM has been successfully implemented as a short summer workshop to introduce computing practices in microbiome analysis. Based on self-assessed student knowledge of topics and skills, increased scientific confidence and interest in genomics careers were observed. We propose MEM be incorporated in a scalable course-based research experience for undergraduate institutions, including tribal colleges and universities, community colleges and other minority serving institutions. This coupled curricular and research framework explicitly considers cultural perspectives, access and equity to train a diverse future workforce that is more informed to engage in microbiome research and to translate microbiome science to benefit community and environmental health.

Twenty-eight-day mortality among patients with severe or critical COVID-19 in Hong Kong during the early stages of the pandemic.

INTRODUCTION: In 2020, patients with critical coronavirus disease 2019 (COVID-19) had a 28-day mortality rate of 30% to 50% worldwide; outcomes among such patients in Hong Kong were unknown. This study investigated 28-day mortality and corresponding risk factors among patients with severe or critical COVID-19 in Hong Kong. METHODS: This retrospective cohort study included adult patients with severe or critical COVID-19 who were admitted to three public hospitals in Hong Kong from 22 January to 30 September 2020. Demographics, comorbidities, symptoms, treatment, and outcomes were examined. RESULTS: Among 125 patients with severe or critical COVID-19, 15 (12.0%) died within 28 days. Overall, the median patient age was 64 years; 48.0% and 54.4% of patients had hypertension and obesity, respectively. Respiratory samples were confirmed severe acute respiratory syndrome coronavirus 2 RNA-positive after a median of 3 days. The most common presenting symptom was fever (80.0% of patients); 45.6% and 32.8% of patients received care in intensive care unit and required mechanical ventilation, respectively. In logistic regression analysis comparing 28-day survivors and non-survivors, factors associated with greater 28-day mortality were older age (odds ratio [OR] per 1-year increase in age=1.12, 95% confidence interval [CI]=1.04-1.21; P=0.002), history of stroke (OR=15.96, 95% CI=1.65-154.66; P=0.017), use of renal replacement therapy (OR=15.32, 95% CI=2.67-87.83; P=0.002), and shorter duration of lopinavir-ritonavir treatment (OR per 1-day increase=0.82, 95% CI=0.68-0.98; P=0.034). CONCLUSION: The 28-day mortality rate among patients with severe or critical COVID-19 in Hong Kong was 12.0%. Older age, history of stroke, use of renal replacement therapy, and shorter duration of lopinavir-ritonavir treatment were independent predictors of 28-day mortality.

Effect of Tooth Loss on Cognitive Function among Older Adults in Singapore.

Evidence suggests a longitudinal association between tooth loss and cognitive function. However, the temporality of this association is not well understood. We investigated the effect of several emulated tooth loss prevention scenarios on cognitive function. We used data from 3 waves (baseline: 2009, second wave: 2011-2012, and third wave: 2015) of the Panel on Health and Ageing of Singaporean Elderly (PHASE). PHASE targeted older adults, aged ≥60 y, in Singapore. Number of teeth was used as a time-varying exposure (baseline, second wave). Cognitive function (Short Portable Mental Status Questionnaire score) in the third wave was assessed as the outcome. Multiple time-invariant (baseline) and time-varying (baseline and second wave) covariates were included. The "longitudinal modified treatment policy approach" combined with targeted minimum loss-based estimation was used to define and estimate additive effects of emulated tooth loss prevention scenarios. Emulated scenarios were the following: what if edentate people retained 1 to 4 teeth (scenario 1), what if those with <5 teeth retained 5 to 9 teeth (scenario 2), what if those with <10 teeth retained 10 to 19 teeth (scenario 3), and what if everyone retained ≥20 teeth (scenario 4)? A total of 1,516 participants, excluding those with severe cognitive impairment, were included (male: 41.6%). The mean age at baseline was 70.6 y (SD = 7.1). The mean SPMSQ score at baseline was 2.06 (SD = 0.02) for edentulous, 1.55 (SD = 0.04) for 1 to 4 teeth, 1.61 (SD = 0.03) for 5 to 9 teeth, 1.73 (SD = 0.02) for 10 to 19 teeth, and 1.71 (SD = 0.02) for ≥20 teeth. Additive effect of hypothetical intervention gradually increased with intensity of prevention from scenario 1 to scenario 4 (scenario 1: -0.02 [95% CI, -0.08 to 0.04], scenario 2: -0.05 [95% CI, -0.11 to -0.00], scenario 3: -0.07 [95% CI, -0.14 to -0.00], scenario 4: -0.15 [95% CI, -0.23 to -0.06]). Emulated tooth loss prevention interventions were associated with better cognitive function score. Therefore, preventing tooth loss could potentially benefit maintenance of cognitive function among older adults.

Chinese Preclinical Alzheimer's Disease Study (C-PAS): Design and Challenge from PET Acceptance.

BACKGROUND: Large-scale preclinical Alzheimer's disease study based on ß-amyloid positron emission tomography (PET) has not been conducted in China. OBJECTIVES: Establish a cohort on Alzheimer's disease spectrum, especially the preclinical stages, and determine the factors influencing the acceptance of ß-amyloid PET scan screening in China. DESIGN: Longitudinal. SETTING: Shanghai, China. PARTICIPANTS: A total of 4386 participants were screened and 2451 participants who met enrollment criteria were eventually included in this report. MEASUREMENTS: The multidimensional data was collected, including comprehensive assessments, PET and magnetic resonance imaging scans, genetics, and plasma biomarkers. RESULTS: There were 571 participants in the normal cognition group, 625 participants in the subjective cognitive decline group, 155 participants in the objectively defined subtle cognitive decline group, 501 participants in the mild cognitive impairment group, 471 participants in Alzheimer's disease group, and 128 participants with cognitive impairment from other known causes. Significant differences in demographics, florbetapir PET, APOE, and neuropsychological tests were found among the groups. Eight hundred and seventeen participants (33.3%) completed the florbetapir PET scanning. Non-demented individuals with higher age, lower education years, male, with a family history of dementia, and higher self-report depression prefer to undergo PET scans. Acceptance of PET scans did not correlate with objectively assessed cognitive impairment. CONCLUSIONS: The Chinese Preclinical Alzheimer's Disease Study was designed to establish a large-scale cohort with comprehensive data collection. Our findings may help to understand the factors affecting the acceptance of ß-amyloid PET in urban areas of China and help us address the low acceptance challenge.

A small-molecule PI3Kα activator for cardioprotection and neuroregeneration.

Harnessing the potential beneficial effects of kinase signalling through the generation of direct kinase activators remains an underexplored area of drug development1-5. This also applies to the PI3K signalling pathway, which has been extensively targeted by inhibitors for conditions with PI3K overactivation, such as cancer and immune dysregulation. Here we report the discovery of UCL-TRO-1938 (referred to as 1938 hereon), a small-molecule activator of the PI3Kα isoform, a crucial effector of growth factor signalling. 1938 allosterically activates PI3Kα through a distinct mechanism by enhancing multiple steps of the PI3Kα catalytic cycle and causes both local and global conformational changes in the PI3Kα structure. This compound is selective for PI3Kα over other PI3K isoforms and multiple protein and lipid kinases. It transiently activates PI3K signalling in all rodent and human cells tested, resulting in cellular responses such as proliferation and neurite outgrowth. In rodent models, acute treatment with 1938 provides cardioprotection from ischaemia-reperfusion injury and, after local administration, enhances nerve regeneration following nerve crush. This study identifies a chemical tool to directly probe the PI3Kα signalling pathway and a new approach to modulate PI3K activity, widening the therapeutic potential of targeting these enzymes through short-term activation for tissue protection and regeneration. Our findings illustrate the potential of activating kinases for therapeutic benefit, a currently largely untapped area of drug development.

Phase Ib study of talimogene laherparepvec in combination with atezolizumab in patients with triple negative breast cancer and colorectal cancer with liver metastases.

BACKGROUND: Talimogene laherparepvec (T-VEC), a first-in-class oncolytic viral immunotherapy, enhances tumor-specific immune activation. T-VEC combined with atezolizumab, which blocks inhibitor T-cell checkpoints, could provide greater benefit than either agent alone. Safety/efficacy of the combination was explored in patients with triple negative breast cancer (TNBC) or colorectal cancer (CRC) with liver metastases. METHODS: In this phase Ib, multicenter, open-label, parallel cohort study of adults with TNBC or CRC with liver metastases, T-VEC (106 then 108 PFU/ml; ≤4 ml) was administered into hepatic lesions via image-guided injection every 21 (±3) days. Atezolizumab 1200 mg was given on day 1 and every 21 (±3) days thereafter. Treatment continued until patients experienced dose-limiting toxicity (DLT), had complete response, progressive disease, needed alternative anticancer treatment, or withdrew due to an adverse event (AE). The primary endpoint was DLT incidence, and secondary endpoints included efficacy and AEs. RESULTS: Between 19 March 2018 and 6 November 2020, 11 patients with TNBC were enrolled (safety analysis set: n = 10); between 19 March 2018 and 16 October 2019, 25 patients with CRC were enrolled (safety analysis set: n = 24). For the 5 patients in the TNBC DLT analysis set, no patient had DLT; for the 18 patients in the CRC DLT analysis set, 3 (17%) had DLT, all serious AEs. AEs were reported by 9 (90%) TNBC and 23 (96%) CRC patients, the majority with grade ≥3 [TNBC, 7 (70%); CRC, 13 (54%)], and 1 was fatal [CRC, 1 (4%)]. Evidence of efficacy was limited. Overall response rate was 10% (95% confidence interval 0.3-44.5) for TNBC; one (10%) patient had a partial response. For CRC, no patients had a response; 14 (58%) were unassessable. CONCLUSIONS: The safety profile reflected known risks with T-VEC including risks of intrahepatic injection; no unexpected safety findings from addition of atezolizumab to T-VEC were observed. Limited evidence of antitumor activity was observed.

The reorganisation of emergency general surgery services during the COVID-19 pandemic in the UK: outcomes of delayed presentation, socio-economic deprivation and Black, Asian and Minority Ethnic patients.

INTRODUCTION: The COVID-19 pandemic is a global public health emergency. Lockdown restrictions and the reconfiguration of healthcare systems to accommodate an increase in critical care capacity have had an impact on 'non-COVID' specialties. This study characterises the utilisation of emergency general surgery (EGS) services during the UK lockdown period at a university teaching hospital with a catchment population that represents one of the most deprived and ethnically diverse areas in the UK. METHODS: EGS admissions during the UK lockdown period (March to May 2020) were compared with the same period in 2019. Patient demographics were recorded together with clinical presentation, hospital stay and treatment outcomes, and readmission data. RESULTS: The study included 645 patients, comprising 223 in the COVID-19 period and 422 in the non-COVID-19 period. There was no difference in age, sex, comorbidity or socio-economic status. A lower proportion of patients of Black, Asian and Minority Ethnicity (BAME) were admitted during the pandemic (20.6% vs 35.4%, p < 0.05). The duration of symptoms prior to presentation was longer, and admission clinical parameters and serum inflammatory markers. More patients presented with an acute kidney injury (9.9% vs 4.7%, p = 0.012). There was no difference in perioperative outcomes or 30-day mortality, but more patients were readmitted following conservative management (10.6% vs 4.7%, p = 0.023). CONCLUSIONS: The reorganisation of EGS to a senior-led model has been successful in terms of outcomes and access to treatment despite a more unwell population. There was a significantly lower proportion of BAME admissions suggesting additional barriers to healthcare access under pandemic lockdown conditions.

Pembrolizumab monotherapy versus chemotherapy in platinum-pretreated, recurrent or metastatic nasopharyngeal cancer (KEYNOTE-122): an open-label, randomized, phase III trial.

BACKGROUND: Pembrolizumab previously demonstrated robust antitumor activity and manageable safety in a phase Ib study of patients with heavily pretreated, programmed death ligand 1 (PD-L1)-positive, recurrent or metastatic nasopharyngeal carcinoma (NPC). The phase III KEYNOTE-122 study was conducted to further evaluate pembrolizumab versus chemotherapy in patients with platinum-pretreated, recurrent and/or metastatic NPC. Final analysis results are presented. PATIENTS AND METHODS: KEYNOTE-122 was an open-label, randomized study conducted at 29 sites, globally. Participants with platinum-pretreated recurrent and/or metastatic NPC were randomly assigned (1 : 1) to pembrolizumab or chemotherapy with capecitabine, gemcitabine, or docetaxel. Randomization was stratified by liver metastasis (present versus absent). The primary endpoint was overall survival (OS), analyzed in the intention-to-treat population using the stratified log-rank test (superiority threshold, one-sided P = 0.0187). Safety was assessed in the as-treated population. RESULTS: Between 5 May 2016 and 28 May 2018, 233 participants were randomly assigned to treatment (pembrolizumab, n = 117; chemotherapy, n = 116); Most participants (86.7%) received study treatment in the second-line or later setting. Median time from randomization to data cut-off (30 November 2020) was 45.1 months (interquartile range, 39.0-48.8 months). Median OS was 17.2 months [95% confidence interval (CI) 11.7-22.9 months] with pembrolizumab and 15.3 months (95% CI 10.9-18.1 months) with chemotherapy [hazard ratio, 0.90 (95% CI 0.67-1.19; P = 0.2262)]. Grade 3-5 treatment-related adverse events occurred in 12 of 116 participants (10.3%) with pembrolizumab and 49 of 112 participants (43.8%) with chemotherapy. Three treatment-related deaths occurred: 1 participant (0.9%) with pembrolizumab (pneumonitis) and 2 (1.8%) with chemotherapy (pneumonia, intracranial hemorrhage). CONCLUSION: Pembrolizumab did not significantly improve OS compared with chemotherapy in participants with platinum-pretreated recurrent and/or metastatic NPC but did have manageable safety and a lower incidence of treatment-related adverse events.

Classification of Protein-Binding Sites Using a Spherical Convolutional Neural Network.

The analysis and comparison of protein-binding sites aid various applications in the drug discovery process, e.g., hit finding, drug repurposing, and polypharmacology. Classification of binding sites has been a hot topic for the past 30 years, and many different methods have been published. The rapid development of machine learning computational algorithms, coupled with the large volume of publicly available protein-ligand 3D structures, makes it possible to apply deep learning techniques in binding site comparison. Our method uses a cutting-edge spherical convolutional neural network based on the DeepSphere architecture to learn global representations of protein-binding sites. The model was trained on TOUGH-C1 and TOUGH-M1 data and validated with the ProSPECCTs datasets. Our results show that our model can (1) perform well in protein-binding site similarity and classification tasks and (2) learn and separate the physicochemical properties of binding sites. Lastly, we tested the model on a set of kinases, where the results show that it is able to cluster the different kinase subfamilies effectively. This example demonstrates the method's promise for lead hopping within or outside a protein target, directly based on binding site information.