Developing Priorities for Palliative Care Research in Advanced Liver Disease: A Multidisciplinary Approach.

Individuals with advanced liver disease (AdvLD), such as decompensated cirrhosis (DC) and hepatocellular carcinoma (HCC), have significant palliative needs. However, little research is available to guide health care providers on how to improve key domains related to palliative care (PC). We sought to identify priority areas for future research in PC by performing a comprehensive literature review and conducting iterative expert panel discussions. We conducted a literature review using search terms related to AdvLD and key PC domains. Individual reviews of these domains were performed, followed by iterative discussions by a panel consisting of experts from multiple disciplines, including hepatology, specialty PC, and nursing. Based on these discussions, priority areas for research were identified. We identified critical gaps in the available research related to PC and AdvLD. We developed and shared five key priority questions incorporating domains related to PC. Conclusion: Future research endeavors focused on improving PC in AdvLD should consider addressing the five key priorities areas identified from literature reviews and expert panel discussions.

Effect of Concomitant Therapy With Steroids and Tumor Necrosis Factor Antagonists for Induction of Remission in Patients With Crohn's Disease: A Systematic Review and Pooled Meta-analysis.

BACKGROUND & AIMS: It is not clear whether concomitant therapy with corticosteroids and anti-tumor necrosis factor (TNF) agents is more effective at inducing remission in patients with Crohn's disease (CD) than anti-TNF monotherapy. We aimed to determine whether patients with active CD receiving corticosteroids during induction therapy with anti-TNF agents had higher rates of clinical improvement than patients not receiving corticosteroids during induction therapy. METHODS: We systematically searched the MEDLINE, Embase, and CENTRAL databases, through January 20, 2016, for randomized trials of anti-TNF agents approved for treatment of CD and identified 14 trials (5 of adalimumab, 5 of certolizumab, and 4 of infliximab). We conducted a pooled meta-analysis of individual patient and aggregated data from these trials. We compared data from participants who continued oral corticosteroids during induction with anti-TNF therapy to those treated with anti-TNF agents alone. The endpoints were clinical remission (CD activity index [CDAI] scores <150) and clinical response (a decrease in CDAI of 100 points) at the end of induction (weeks 4-14 of treatment). RESULTS: We included 4354 patients who received induction therapy with anti-TNF agents, including 1653 [38.0%] who were receiving corticosteroids. The combination of corticosteroids and an anti-TNF agent induced clinical remission in 32.0% of patients, whereas anti-TNF monotherapy induced clinical remission in 35.5% of patients (odds ratio [OR], 0.93; 95% CI, 0.74-1.17). The combination of corticosteroids and an anti-TNF agent induced a clinical response in 42.7% of patients, whereas anti-TNF monotherapy induced a clinical response in 46.8% (OR 0.84; 95% CI, 0.73-0.96). These findings did not change with adjustment for baseline CDAI scores and concurrent use of immunomodulators. CONCLUSIONS: Based on a meta-analysis of data from randomized trials of anti-TNF therapies in patients with active CD, patients receiving corticosteroids during induction therapy with anti-TNF agents did not have higher rates of clinical improvement compared with patients not receiving corticosteroids during induction therapy. Given these findings and the risks of corticosteroid use, clinicians should consider early weaning of corticosteroids during induction therapy with anti-TNF agents for patients with corticosteroid-refractory CD.

Genetic Mutations in Young Nonsmoking Patients With Oral Cavity Cancer: A Systematic Review.

OBJECTIVE: This investigation aims to review the known genetic mutations associated with oral cavity squamous cell carcinoma (OCSCC) in young adults with limited environmental risk factors (YLERs). DATA SOURCES: A comprehensive search strategy was designed to identify studies in MEDLINE (Ovid), Embase (Ovid), and Scopus from database inception to May 2017 that included adults ≤50 years of age with OCSCC and minimal tobacco use history (≤10 pack-years) who had their tumors genetically sequenced or mutational profiles analyzed. REVIEW METHODS: Identified articles were screened by 2 reviewers. Quality of evidence was graded by the MINORS criteria for case-control studies; other studies were graded by assigning a level of evidence for gene mutation literature. RESULTS: Thirteen studies met our inclusion criteria, and 130 patients met our criteria for age and tobacco history. TP53 was the most commonly evaluated gene (10 of 13 studies) and the most frequently observed mutation. One study reported that nonsmokers had significantly fewer TP53 mutations, while 9 studies found no difference in the prevalence of TP53 mutations. No other mutations were found specific to this cohort. CONCLUSIONS: TP53 mutations may occur at a similar rate in YLERs with OCSCC as compared with older patients or those with risk factors. However, few studies have aimed to characterize the genetic landscape of oral cavity tumors in this population, often with small sample sizes. Future studies are needed to explore unidentified genetic alterations leading to tumor susceptibility or alternative mechanisms of carcinogenesis.

Cytokine elevation in severe and critical COVID-19: a rapid systematic review, meta-analysis, and comparison with other inflammatory syndromes.

The description of a so-called cytokine storm in patients with COVID-19 has prompted consideration of anti-cytokine therapies, particularly interleukin-6 antagonists. However, direct systematic comparisons of COVID-19 with other critical illnesses associated with elevated cytokine concentrations have not been reported. In this Rapid Review, we report the results of a systematic review and meta-analysis of COVID-19 studies published or posted as preprints between Nov 1, 2019, and April 14, 2020, in which interleukin-6 concentrations in patients with severe or critical disease were recorded. 25 COVID-19 studies (n=1245 patients) were ultimately included. Comparator groups included four trials each in sepsis (n=5320), cytokine release syndrome (n=72), and acute respiratory distress syndrome unrelated to COVID-19 (n=2767). In patients with severe or critical COVID-19, the pooled mean serum interleukin-6 concentration was 36·7 pg/mL (95% CI 21·6-62·3 pg/mL; I2=57·7%). Mean interleukin-6 concentrations were nearly 100 times higher in patients with cytokine release syndrome (3110·5 pg/mL, 632·3-15 302·9 pg/mL; p<0·0001), 27 times higher in patients with sepsis (983·6 pg/mL, 550·1-1758·4 pg/mL; p<0·0001), and 12 times higher in patients with acute respiratory distress syndrome unrelated to COVID-19 (460 pg/mL, 216·3-978·7 pg/mL; p<0·0001). Our findings question the role of a cytokine storm in COVID-19-induced organ dysfunction. Many questions remain about the immune features of COVID-19 and the potential role of anti-cytokine and immune-modulating treatments in patients with the disease.

Ibrutinib dose modifications in the management of CLL.

BACKGROUND: Ibrutinib is a Bruton tyrosine kinase inhibitor approved for the treatment of chronic lymphocytic leukemia (CLL) in 2014. Ibrutinib is often used to treat patients who are younger than the patients originally included in theclinical trials have additional unfavorable prognostic factors and suffer from additional comorbidities excluded from the original phase III trials. Our objective was to examine current clinical practices and their impact in this expanded population of CLL patients who often require adjustments in the standard prescribed dose and schedule of therapy. MATERIALS AND METHODS: An extensive review of the medical literature was conducted to establish the consensus on ibrutinib dose modifications in patients with CLL. Twenty-nine studies were reviewed including fourteen clinical trials and fifteen "real-world practice" studies. RESULTS: The average discontinuation rate was similar between clinical trials and "real-world practice" studies though the reasons for discontinuation differed. CLL progression was a more common reason for discontinuation in clinical trial studies while toxicity was a more common reason for discontinuation in "real-world practice" studies. Some studies have suggested worse outcomes in patients requiring dose reductions in ibrutinib while others have shown no change in treatment efficacy in patients requiring dose reductions due to concomitant CYP medications or increased immunosuppression post-transplant. CONCLUSION: The impact of ibrutinib dose modifications on clinical outcome remains unclear. Patients on concomitant CYP3A inhibitors should be prescribed a lower dose than the standard 420 mg daily, in order to maintain comparable pharmacologic properties. Further research is required to establish definitive clinical practice guidelines.

Survival after Metastasectomy for Metastatic Urothelial Carcinoma: A Systematic Review and Meta-Analysis.

Background: Cisplatin-based combination chemotherapy is standard treatment for metastatic urothelial carcinoma; however, the vast majority of patients experience disease progression. As systemic therapy alone is rarely curative for the treatment of metastatic urothelial cancer, not only are new therapies needed but also refinement of general treatment principles. Herein, we conducted a systematic review and meta-analysis to explore the role of metastasectomy in metastatic urothelial carcinoma. Methods: We conducted a systematic review of the literature regarding local treatment for metastatic urothelial carcinoma. An online electronic search of the PubMed/MEDLINE and EMBASE databases was performed to identify peer-reviewed articles. All procedures were performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Information was then extracted including number of patients, gender, the site of the primary urothelial tumor, site of metastasis, chemotherapy before or after metastasectomy, overall survival (OS), and disease specific survival (DSS) after metastasectomy. A meta-analysis was performed with those studies with sufficient survival data to obtain pooled overall survival. The article quality was assessed using the Cochrane Handbook "risk of bias" tool. Results: Seventeen out of 3963 articles were eligible for review between 1990-2015, including a total of 412 patients. The mean time to recurrence after metastasectomy was 14.25 months. The overall survival from time of metastasectomy ranged from 2 to 60 months. Pooled analyses of studies reported survival data revealed an improved overall survival for patients treated with metastasectomy compared with non-surgical treatment of metastatic lesions (HR 0.63; 95% CI, 0.49-0.81). All, except for three studies, were retrospective and non-randomized, leading to a high risk of bias associated with patient selection, patient attrition, and reporting. Such high potential of selection bias may lead to higher OS than expected. Additionally, treatment and outcome details reported across studies was highly variable. Conclusions: Limited conclusions can be drawn from the available literature exploring the role of metastasectomy in the management of metastatic urothelial cancer due to lack of uniform reporting elements and multiple sources of bias particularly related to a lack of prospective randomized trials. As a subset of patients treated with metastasectomy achieve durable disease control, this approach may be considered for select patients.