The Implications of Treatment Delays in Adjuvant Therapy for Resected Cholangiocarcinoma Patients.

PURPOSE: The purpose of this study is to understand factors associated with timing of adjuvant therapy for cholangiocarcinoma and the impact of delays on overall survival (OS). METHODS: Data from the National Cancer Database (NCDB) for patients with non-metastatic bile duct cancer from 2004 to 2015 were analyzed. Patients were included only if they underwent surgery and adjuvant chemotherapy and/or radiotherapy (RT). Patients who underwent neoadjuvant or palliative treatments were excluded. Pearson's chi-squared test and multivariate logistic regression analyses were used to assess the distribution of demographic, clinical, and treatment factors. After propensity score matching with inverse probability of treatment weighting, OS was compared between patients initiating therapy past various time points using Kaplan Meier analyses and doubly robust estimation with multivariate Cox proportional hazards modeling. RESULTS: In total, 7,733 of 17,363 (45%) patients underwent adjuvant treatment. The median time to adjuvant therapy initiation was 59 days (interquartile range 45-78 days). Age over 65, black and Hispanic race, and treatment with RT alone were associated with later initiation of adjuvant treatment. Patients with larger tumors and high-grade disease were more likely to initiate treatment early. After propensity score weighting, there was an OS decrement to initiation of treatment beyond the median of 59 days after surgery. CONCLUSIONS: We identified characteristics that are related to the timing of adjuvant therapy in patients with biliary cancers. There was an OS decrement associated with delays beyond the median time point of 59 days. This finding may be especially relevant given the treatment delays seen as a result of COVID-19.

Highly Thermotolerant SARS-CoV-2 Vaccine Elicits Neutralising Antibodies Against Delta and Omicron in Mice (preprint)

As the existing vaccines do not completely prevent infections or community transmission of the coronavirus disease-19 (COVID-19), there is an unmet need for vaccines that can better combat severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) variants of concern (VOC) and also eliminate cold chain requirements. We show that highly thermo-tolerant monomeric and trimeric receptor binding domain derivatives that can withstand 100C for 90 minutes and 37C for four weeks elicit high antibody titres in mice that received prime-boost immunization on Days 0 and 21; and that these antibodies neutralize SARS-CoV-2 variants VIC31 (containing the Spike D614G mutation), Delta and Omicron (BA.1.1) VOC. Compared to VIC31, there was an average 14.4-fold reduction in neutralization against BA.1.1 for the three monomeric, and 16.5-fold re-duction for the three trimeric antigen-adjuvant combinations; the corresponding values against Delta were 2.5 and 3.0. Our findings suggest that monomeric formulations are suitable for the upcoming Phase I human clinical trials, and that there is potential for improving efficacy with vaccine matching to improve responses against emerging variants. These findings are consistent with in silico modelling and AlphaFold predictions which show that while oligomeric presentation can be generally beneficial, it can make important epitopes inaccessible.

At least three doses of leading vaccines essential for neutralization of SARS-CoV-2 Omicron variant (preprint)

Plasma samples taken at different time points from donors who received either AstraZeneca (Vaxzevria) or Pfizer (Comirnaty) or Moderna (Spikevax) coronavirus disease-19 (COVID-19) vaccine were assessed in virus neutralization assays against Delta and Omicron variants of concern and a reference isolate (VIC31). With the Pfizer vaccine there was 6-8 fold reduction in 50% neutralizing antibody titres (NT50) against Delta and VIC31 at 6 months compared to 2 weeks after the second dose; followed by 25-fold increase at 2 weeks after the third dose. Neutralisation of Omicron was only consistently observed 2 weeks after the third dose, with most samples having titres below the limit of detection at earlier timepoints. Moderna results were similar to Pfizer at 2 weeks after the second dose, while the titres for AstraZeneca samples derived from older donors were 7-fold lower against VIC31 and below the limit of detection against Delta and Omicron. Age and gender were not found to significantly impact our results. These observations indicate that vaccine matching may be needed, and that at least a third dose of these vaccines is necessary to generate sufficient neutralising antibodies against emerging variants of concern, especially Omicron, amidst the challenges of ensuring vaccine equity worldwide.

Fatty Liver and the Coronavirus Disease 2019 Pandemic: Health Behaviors, Social Factors, and Telemedicine Satisfaction in Vulnerable Populations.

The coronavirus disease 2019 (COVID-19) pandemic has impacted health-related behaviors that influence fatty liver disease (FLD) management. We evaluated the impact of the pandemic on FLD management and satisfaction with care delivery in this population. In the San Francisco safety-net hepatology clinics, we evaluated health-related behaviors and factors associated with self-reported weight gain during the COVID-19 pandemic as well as satisfaction with telemedicine in adults with FLD by using multivariable modeling. From June 1, 2020, to May 5, 2021, 111 participants were enrolled. Median age was 52 years, 30% were men, 63% were Hispanic, 21% were Asian/Pacific Islander, and 9% were White. Eating habits were unchanged or healthier for 80%, physical activity decreased in 51%, 34% reported weight gain, and 5% reported increased alcohol intake. Forty-five percent had severe depressive symptoms, 38% in those without diagnosed depression and 60% of individuals with heavy alcohol use. On multivariable analysis, decreased physical activity (odds ratio [OR], 4.8) and heavy alcohol use (OR, 3.4) were associated with weight gain (all P < 0.05). Among those with telemedicine visits (n = 66), 62% reported being very satisfied. Hispanic ethnicity was associated with a 0.8-unit decrease in the telemedicine satisfaction score (P = 0.048) when adjusting for sex, age, and pandemic duration. Conclusion: During the pandemic, decreased physical activity and heavy alcohol use were most influential on self-reported weight gain in FLD. Maintenance of healthy eating and increased physical activity, alcohol cessation counseling, and mental health services are critical in preventing poor FLD-associated outcomes during the pandemic recovery. Dissatisfaction with telemedicine should be explored further to ensure equitable care, especially among the vulnerable Hispanic population.

Live virus neutralisation of the 501Y.V1 and 501Y.V2 SARS-CoV-2 variants following INO-4800 vaccination of ferrets (preprint)

The ongoing COVID-19 pandemic has resulted in significant global morbidity and mortality on a scale similar to the influenza pandemic of 1918. Over the course of the last few months, a number of SARS-CoV-2 variants have been identified against which vaccine-induced immune responses may be less effective. These variants-of-concern have garnered significant attention in the media, with discussion around their impact on the future of the pandemic and the ability of leading COVID-19 vaccines to protect against them effectively. To address concerns about emerging SARS-CoV-2 variants affecting vaccine-induced immunity, we investigated the neutralisation of representative G614, 501Y.V1 and 501Y.V2 virus isolates using sera from ferrets that had received prime-boost doses of the DNA vaccine, INO-4800. Neutralisation titres against G614 and 501Y.V1 were comparable, but titres against the 501Y.V2 variant were approximately 4-fold lower, similar to results reported with other nucleic acid vaccines and supported by in silico biomolecular modelling. The results confirm that the vaccine-induced neutralising antibodies generated by INO-4800 remain effective against current variants-of-concern, albeit with lower neutralisation titres against 501Y.V2 similar to other leading nucleic acid-based vaccines.