Patterns and outcomes of subsequent therapy after immune checkpoint inhibitor discontinuation in HCC

The availability of immune checkpoint inhibitors (ICIs) for the management of advanced hepatocellular cancer (HCC) has changed the treatment paradigm. There are emerging questions regarding the efficacy of subsequent anticancer therapies. The primary aim of this retrospective, multicenter study was to examine the types of anticancer treatment received after ICIs and to assess the impact on post-ICI survival. We established an international consortium of 11 tertiary-care referral centers located in the USA (n = 249), Europe (n = 74), and Asia (n = 97), and described patterns of care following ICI therapy. The impact of subsequent therapy on overall survival (OS) was estimated using the Kaplan–Meier method and presented with a 95% confidence interval (CI). A total of 420 patients were treated with ICIs for advanced HCC after one line of systemic therapy (n = 371, 88.8%): 31 (8.8%) had died, 152 (36.2%) received best supportive care (BSC) following ICIs, and 163 patients (38.8%) received subsequent anticancer therapy. Tyrosine kinase inhibitors (TKIs, n = 132, 80.9%), in particular sorafenib (n = 49, 30.0%), were the most common post-ICI therapy followed by external beam radiotherapy (n = 28, 17.2%), further immunotherapy (n = 21, 12.9%), locoregional therapy (n = 23, 14.1%), chemotherapy (n = 9, 5.5%), and surgery (n = 6, 3.6%). Receipt of post-ICI therapy was associated with longer median OS compared with those who had received BSC (12.1 vs. 3.3 months; hazard ratio [HR]: 0.4 (95% CI: 2.7–5.0). No difference in OS was noted in those patients who received TKI before ICIs compared with those who received ICIs followed by TKI. Conclusion: Post-ICI therapy is associated with OS in excess of 12 months, suggesting a role for therapeutic sequencing. OS from TKI therapy was similar to that reported in registration studies, suggesting preserved efficacy following ICIs

Impact of older age in patients receiving atezolizumab and bevacizumab for hepatocellular carcinoma

Background and Aims Combination atezolizumab/bevacizumab is the gold standard for first-line treatment of unresectable hepatocellular carcinoma (HCC). Our study investigated the efficacy and safety of combination therapy in older patients with HCC. Methods 191 consecutive patients from eight centres receiving atezolizumab and bevacizumab were included. Overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and disease control rate (DCR) defined by RECIST v1.1 were measured in older (age ≥ 65 years) and younger (age < 65 years) age patients. Treatment-related adverse events (trAEs) were evaluated. Results The elderly (n = 116) had higher rates of non-alcoholic fatty liver disease (19.8% vs. 2.7%; p < .001), presenting with smaller tumours (6.2 cm vs 7.9 cm, p = .02) with less portal vein thrombosis (31.9 vs. 54.7%, p = .002), with fewer patients presenting with BCLC-C stage disease (50.9 vs. 74.3%, p = .002). There was no significant difference in OS (median 14.9 vs. 15.1 months; HR 1.15, 95% CI 0.65–2.02 p = .63) and PFS (median 7.1 vs. 5.5 months; HR 1.11, 95% CI 0.54–1.92; p = .72) between older age and younger age. Older patients had similar ORR (27.6% vs. 20.0%; p = .27) and DCR (77.5% vs. 66.1%; p = .11) compared to younger patients. Atezolizumab-related (40.5% vs. 48.0%; p = .31) and bevacizumab-related (44.8% vs. 41.3%; p = .63) trAEs were comparable between groups. Rates of grade ≥3 trAEs and toxicity-related treatment discontinuation were similar between older and younger age patients. Patients 75 years and older had similar survival and safety outcomes compared to younger patients. Conclusions Atezolizumab and bevacizumab therapy is associated with comparable efficacy and tolerability in older age patients with unresectable HCC

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Prospective, multicentre study of screening, investigation and management of hyponatraemia after subarachnoid haemorrhage in the UK and Ireland

Background: Hyponatraemia often occurs after subarachnoid haemorrhage (SAH). However, its clinical significance and optimal management are uncertain. We audited the screening, investigation and management of hyponatraemia after SAH. Methods: We prospectively identified consecutive patients with spontaneous SAH admitted to neurosurgical units in the United Kingdom or Ireland. We reviewed medical records daily from admission to discharge, 21 days or death and extracted all measurements of serum sodium to identify hyponatraemia (&lt;135 mmol/L). Main outcomes were death/dependency at discharge or 21 days and admission duration &gt;10 days. Associations of hyponatraemia with outcome were assessed using logistic regression with adjustment for predictors of outcome after SAH and admission duration. We assessed hyponatraemia-free survival using multivariable Cox regression. Results: 175/407 (43%) patients admitted to 24 neurosurgical units developed hyponatraemia. 5976 serum sodium measurements were made. Serum osmolality, urine osmolality and urine sodium were measured in 30/166 (18%) hyponatraemic patients with complete data. The most frequently target daily fluid intake was &gt;3 L and this did not differ during hyponatraemic or non-hyponatraemic episodes. 26% (n/N=42/164) patients with hyponatraemia received sodium supplementation. 133 (35%) patients were dead or dependent within the study period and 240 (68%) patients had hospital admission for over 10 days. In the multivariable analyses, hyponatraemia was associated with less dependency (adjusted OR (aOR)=0.35 (95% CI 0.17 to 0.69)) but longer admissions (aOR=3.2 (1.8 to 5.7)). World Federation of Neurosurgical Societies grade I–III, modified Fisher 2–4 and posterior circulation aneurysms were associated with greater hazards of hyponatraemia. Conclusions: In this comprehensive multicentre prospective-adjusted analysis of patients with SAH, hyponatraemia was investigated inconsistently and, for most patients, was not associated with changes in management or clinical outcome. This work establishes a basis for the development of evidence-based SAH-specific guidance for targeted screening, investigation and management of high-risk patients to minimise the impact of hyponatraemia on admission duration and to improve consistency of patient care

Effectiveness and safety of ferric carboxymaltose compared to iron sucrose in women with iron deficiency anemia: phase IV clinical trials

Abstract Background Iron deficiency anemia (IDA) is a significant problem worldwide particularly in women. The aim of the study was to evaluate the effectiveness and safety of intravenous ferric carboxymaltose (FCM) in comparison to iron sucrose (IS) in women with IDA. Method Two hundred patients at Department of Obstetrics and Gynaecology, Sher-i-Kashmir Institute of Medical Sciences Medical College and Hospital, Jammu & Kashmir, India identified with IDA were enrolled for the study. Intravenous FCM and IS were both given as per the protocol. Change in the laboratory parameters such as hemoglobin (Hb), mean corpuscular value, and serum ferritin levels at two weeks and four weeks interval after the treatment was recorded. Result A significant increase in the mean Hb was observed from 7.76 ± 0.709 to 13.25 ± 0.606 in patients treated with FCM and 7.64 ± 0.710 to 11.59 ± 0.733 g/dL (P < 0.001) in patients treated with IS after four weeks of therapy. The rise in mean corpuscular volume was from 66.82 ± 5.24 to 86.76 ± 3.765 and 68.05 ± 5.56 to 93.80 ± 3.80 and rise in serum ferritin levels were from 8.32 ± 1.787 to 38.94 ± 6.095 μg/L and 8.16 ± 1.540 to 27 ± 8.175 μg/L in patients treated with FCM and IS respectively after four weeks of therapy. No serious adverse effects were reported. Conclusion Parenteral therapy is effective in IDA, but FCM elevates hemoglobin level and restored iron stores faster than IS with minimum adverse drug reactions. Trial registration number ISRCTN14484575 Dated: 15–12-2017 retrospectively registered. https://doi.org/10.1186/ISRCTN1448457

Seismic Performance Assessment of the Historical Reggio Calabria Cathedral

Background: Italy's church buildings' cultural and architectural significance cannot be overstated. Objective: This paper addresses the seismic vulnerability of the cathedral located in Reggio Calabria, Italy. The analysis of this building is interesting as it was retrofitted after the destructive 1908 Messina-Reggio Calabria earthquake. Methods: The original design illustrating the static schemes and the considered actions of the church are described. Structural drawings of that time are also reported, which proved to be fundamental for the numerical modelling of the building. The issues and assumptions made during the modelling phase of the structure with the seismic actions are also illustrated. All the transverse and longitudinal frames were analysed using nonlinear analysis to evaluate the seismic capacity and vulnerability indicators in terms of accelerations and periods. Results: The results provided by the modal analysis are presented and discussed to highlight the global dynamic behaviour of the church. Conclusion: The seismic vulnerability indicators have been calculated by considering the seismic actions recommended by the current technical standards and concerning the 1975 Messina earthquake, which represents the most severe earthquake experienced by the church

Lipid profiles of Threadfin bream (<i style="">Nemipterus japonicus</i>) organs

461-463Present study of the lipid content in different organs of marine fish Threadfin bream (Nemipterus japonicus) indicates that a major amount of lipids are accumulated in liver (6.22%) when compared with remaining organs like muscle (2.7%) and skin (1.0%). Cholesterol studies reveal that muscle (36.2%) is having more quantities than liver (32.4%) and skin (24%). Fatty acid composition reveals that the lipids of each organ of threadfin bream are enriched in the unsaturated fatty acids and all the organs were found to be rich in linoleic (C18: 2), oleic (C 18:1) and palmitic (C16: 0). The present study further elucidates that a considerable amount of two physiologically important n-3 PUFAs, i.e. EPA and DHA were found more in skin (1.6% and 0.5%) and liver (1.6% and 0.6%) than in muscle (1.4% and 0.4%)

Discovering untapped microbial communities through metagenomics for microplastic remediation: recent advances, challenges, and way forward

Microplastics (MPs) are ubiquitous pollutants persisting almost everywhere in the environment. With the increase in anthropogenic activities, MP accumulation is increasing enormously in aquatic, marine, and terrestrial ecosystems. Owing to the slow degradation of plastics, MPs show an increased biomagnification probability of persistent, bioaccumulative, and toxic substances thereby creating a threat to environmental biota. Thus, remediation of MP-pollutants requires efficient strategies to circumvent the mobilization of contaminants leaching into the water, soil, and ultimately to human beings. Over the years, several microorganisms have been characterized by the potential to degrade different plastic polymers through enzymatic actions. Metagenomics (MGs) is an effective way to discover novel microbial communities and access their functional genetics for the exploration and characterization of plastic-degrading microbial consortia and enzymes. MGs in combination with metatranscriptomics and metabolomics approaches are a powerful tool to identify and select remediation-efficient microbes in situ. Advancement in bioinformatics and sequencing tools allows rapid screening, mining, and prediction of genes that are capable of polymer degradation. This review comprehensively summarizes the growing threat of microplastics around the world and highlights the role of MGs and computational biology in building effective response strategies for MP remediation

Association Between Immune-Related Adverse Events and Clinical Outcomes to Programmed Cell Death Protein 1/Programmed Death-Ligand 1 Blockade in SCLC

Introduction: The development of immune-related adverse events (irAEs) has been associated with improved efficacy of immune checkpoint inhibitors in patients with urothelial cancer, melanoma, and NSCLC. Whether this association exists in patients with SCLC is currently unknown. Methods: We conducted a multicenter retrospective study to evaluate the relationship between irAEs and immunotherapy efficacy in SCLC. To account for the lead-time bias resulting from the time-dependent nature of irAEs, the development of irAEs was considered as a time-varying covariate in univariate and multivariate Cox proportional hazard models. Results: Of the 183 patients treated with immunotherapy, 73 (39.9%) experienced at least one irAE. A total of 42 patients (22.9%) had grade 1 to 2 irAEs, whereas 31 patients (16.9%) had grade 3 to 4 irAEs. The median time of onset to the first irAE was 24 days (interquartile range: 14–55). The baseline clinicopathologic features were well-balanced between patients with and without irAEs. At a median follow-up of 24 months (95% confidence interval [CI]: 17.0–31.6), the median progression-free survival was significantly longer in the irAE group than the non-irAE group (3.8 versus 1.3 mo, p &lt; 0.0001). The median overall survival was also significantly longer among patients with irAEs than patients without irAEs (13.8 versus 2.9 mo, p &lt; 0.0001). When analyzed as a time-varying covariate, the development of irAEs was associated with a significant improvement in progression-free survival (hazard ratio: 0.44 [95% CI: 0.29–0.66], p &lt; 0.001) and overall survival (hazard ratio: 0.47 [95% CI: 0.32–0.71], p &lt; 0.001) in multivariate models. Conclusions: The development of irAEs is associated with improved clinical outcomes for immunotherapy in patients with advanced SCLC