Mayo Clinic Hospital

Rhinosinusitis is a significant and increasing health problem which results in a large financial burden on society. This evidence based position paper describes what is known about rhinosinusitis and nasal polyps, offers evidence based recommendations on diagnosis and treatment, and considers how we can make progress with research in this area. Rhinitis and sinusitis usually coexist and are concurrent in most individuals; thus, the correct terminology is now rhinosinusitis. Rhinosinusitis (including nasal polyps) is defined as inflammation of the nose and the paranasal sinuses characterised by two or more symptoms, one of which should be either nasal blockage/obstruction/congestion or nasal discharge (anterior/posterior nasal drip), +/- facial pain/pressure, +/- reduction or loss of smell; and either endoscopic signs of polyps and/or mucopurulent discharge primarily from middle meatus and/or; oedema/mucosal obstruction primarily in middle meatus, and/or CT changes showing mucosal changes within the ostiomeatal complex and/or sinuses. The paper gives different definitions for epidemiology, first line and second line treatment and for research. Furthermore the paper describes the anatomy and (patho)physiology, epidemiology and predisposing factors, inflammatory mechanisms, evidence based diagnosis, medical and surgical treatment in acute and chronic rhinosinusitis and nasal polyposis in adults and children. Evidence based schemes for diagnosis and treatment are given for the first and second line clinicians. Moreover attention is given to complications and socio-economic cost of chronic rhinosinusitis and nasal polyps. Last but not least the relation to the lower airways is discussed.

The American Society of Echocardiography is accredited by the

peer reviewed

Abstract Background This is the fourth updated Enhanced Recovery After Surgery (ERAS ® ) Society guideline presenting a consensus for optimal perioperative care in colorectal surgery and providing graded recommendations for each ERAS item within the ERAS ® protocol. Methods A wide database search on English literature publications was performed. Studies on each item within the protocol were selected with particular attention paid to meta‐analyses, randomised controlled trials and large prospective cohorts and examined, reviewed and graded according to Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system. Results All recommendations on ERAS ® protocol items are based on best available evidence; good‐quality trials; meta‐analyses of good‐quality trials; or large cohort studies. The level of evidence for the use of each item is presented accordingly. Conclusions The evidence base and recommendation for items within the multimodal perioperative care pathway are presented by the ERAS ® Society in this comprehensive consensus review.

BACKGROUND: Mutations in the gene encoding isocitrate dehydrogenase 1 ( IDH1) occur in 6 to 10% of patients with acute myeloid leukemia (AML). Ivosidenib (AG-120) is an oral, targeted, small-molecule inhibitor of mutant IDH1. METHODS: We conducted a phase 1 dose-escalation and dose-expansion study of ivosidenib monotherapy in IDH1-mutated AML. Safety and efficacy were assessed in all treated patients. The primary efficacy population included patients with relapsed or refractory AML receiving 500 mg of ivosidenib daily with at least 6 months of follow-up. RESULTS: Overall, 258 patients received ivosidenib and had safety outcomes assessed. Among patients with relapsed or refractory AML (179 patients), treatment-related adverse events of grade 3 or higher that occurred in at least 3 patients were prolongation of the QT interval (in 7.8% of the patients), the IDH differentiation syndrome (in 3.9%), anemia (in 2.2%), thrombocytopenia or a decrease in the platelet count (in 3.4%), and leukocytosis (in 1.7%). In the primary efficacy population (125 patients), the rate of complete remission or complete remission with partial hematologic recovery was 30.4% (95% confidence interval [CI], 22.5 to 39.3), the rate of complete remission was 21.6% (95% CI, 14.7 to 29.8), and the overall response rate was 41.6% (95% CI, 32.9 to 50.8). The median durations of these responses were 8.2 months (95% CI, 5.5 to 12.0), 9.3 months (95% CI, 5.6 to 18.3), and 6.5 months (95% CI, 4.6 to 9.3), respectively. Transfusion independence was attained in 29 of 84 patients (35%), and patients who had a response had fewer infections and febrile neutropenia episodes than those who did not have a response. Among 34 patients who had a complete remission or complete remission with partial hematologic recovery, 7 (21%) had no residual detectable IDH1 mutations on digital polymerase-chain-reaction assay. No preexisting co-occurring single gene mutation predicted clinical response or resistance to treatment. CONCLUSIONS: In patients with advanced IDH1-mutated relapsed or refractory AML, ivosidenib at a dose of 500 mg daily was associated with a low frequency of grade 3 or higher treatment-related adverse events and with transfusion independence, durable remissions, and molecular remissions in some patients with complete remission. (Funded by Agios Pharmaceuticals; ClinicalTrials.gov number, NCT02074839 .).

Background Senescent cells, which can release factors that cause inflammation and dysfunction, the senescence-associated secretory phenotype (SASP), accumulate with ageing and at etiological sites in multiple chronic diseases. Senolytics, including the combination of Dasatinib and Quercetin (D + Q), selectively eliminate senescent cells by transiently disabling pro-survival networks that defend them against their own apoptotic environment. In the first clinical trial of senolytics, D + Q improved physical function in patients with idiopathic pulmonary fibrosis (IPF), a fatal senescence-associated disease, but to date, no peer-reviewed study has directly demonstrated that senolytics decrease senescent cells in humans. Methods In an open label Phase 1 pilot study, we administered 3 days of oral D 100 mg and Q 1000 mg to subjects with diabetic kidney disease ( N = 9; 68·7 ± 3·1 years old; 2 female; BMI:33·9 ± 2·3 kg/m 2 ; eGFR:27·0 ± 2·1 mL/min/1·73m 2 ). Adipose tissue, skin biopsies, and blood were collected before and 11 days after completing senolytic treatment. Senescent cell and macrophage/Langerhans cell markers and circulating SASP factors were assayed. Findings D + Q reduced adipose tissue senescent cell burden within 11 days, with decreases in p16 INK4A -and p21 CIP1 -expressing cells, cells with senescence-associated β-galactosidase activity, and adipocyte progenitors with limited replicative potential. Adipose tissue macrophages, which are attracted, anchored, and activated by senescent cells, and crown-like structures were decreased. Skin epidermal p16 INK4A+ and p21 CIP1+ cells were reduced, as were circulating SASP factors, including IL-1α, IL-6, and MMPs-9 and −12. Interpretation "Hit-and-run" treatment with senolytics, which in the case of D + Q have elimination half-lives <11 h, significantly decreases senescent cell burden in humans. Fund NIH and Foundations. ClinicalTrials.gov Identifier: NCT02848131. Senescence, Frailty, and Mesenchymal Stem Cell Functionality in Chronic Kidney Disease: Effect of Senolytic Agents.

AAPM Task Group 119 has produced quantitative confidence limits as baseline expectation values for IMRT commissioning. A set of test cases was developed to assess the overall accuracy of planning and delivery of IMRT treatments. Each test uses contours of targets and avoidance structures drawn within rectangular phantoms. These tests were planned, delivered, measured, and analyzed by nine facilities using a variety of IMRT planning and delivery systems. Each facility had passed the Radiological Physics Center credentialing tests for IMRT. The agreement between the planned and measured doses was determined using ion chamber dosimetry in high and low dose regions, film dosimetry on coronal planes in the phantom with all fields delivered, and planar dosimetry for each field measured perpendicular to the central axis. The planar dose distributions were assessed using gamma criteria of 3%/3 mm. The mean values and standard deviations were used to develop confidence limits for the test results using the concept confidence limit = /mean/ + 1.96sigma. Other facilities can use the test protocol and results as a basis for comparison to this group. Locally derived confidence limits that substantially exceed these baseline values may indicate the need for improved IMRT commissioning.

OBJECTIVES: This is the first of a pair of studies designed to assess efficacy, safety and tolerability of onabotulinumtoxinA (BOTOX) as headache prophylaxis in adults with chronic migraine. METHODS: The Phase III REsearch Evaluating Migraine Prophylaxis Therapy 1 (PREEMPT 1) is a phase 3 study, with a 24-week, double-blind, parallel-group, placebo-controlled phase followed by a 32-week, open-label phase. Subjects were randomized (1:1) to injections every 12 weeks of onabotulinumtoxinA (155 U-195 U; n = 341) or placebo (n = 338) (two cycles). The primary endpoint was mean change from baseline in headache episode frequency at week 24. RESULTS: No significant between-group difference for onabotulinumtoxinA versus placebo was observed for the primary endpoint, headache episodes (-5.2 vs. -5.3; p = 0.344). Large within-group decreases from baseline were observed for all efficacy variables. Significant between-group differences for onabotulinumtoxinA were observed for the secondary endpoints, headache days (p = .006) and migraine days (p = 0.002). OnabotulinumtoxinA was safe and well tolerated, with few treatment-related adverse events. Few subjects discontinued due to adverse events. CONCLUSIONS: There was no between-group difference for the primary endpoint, headache episodes. However, significant reductions from baseline were observed for onabotulinumtoxinA for headache and migraine days, cumulative hours of headache on headache days and frequency of moderate/severe headache days, which in turn reduced the burden of illness in adults with disabling chronic migraine.

OBJECTIVE: To assess the efficacy, safety, and tolerability of onabotulinumtoxinA (BOTOX) as headache prophylaxis in adults with chronic migraine. BACKGROUND: Chronic migraine is a prevalent, disabling, and undertreated neurological disorder. Few preventive treatments have been investigated and none is specifically indicated for chronic migraine. METHODS: The 2 multicenter, pivotal trials in the PREEMPT: Phase 3 REsearch Evaluating Migraine Prophylaxis Therapy clinical program each included a 24-week randomized, double-blind phase followed by a 32-week open-label phase (ClinicalTrials.gov identifiers NCT00156910, NCT00168428). Qualified patients were randomized (1:1) to onabotulinumtoxinA (155-195 U) or placebo injections every 12 weeks. Study visits occurred every 4 weeks. These studies were identical in design (eg, inclusion/exclusion criteria, randomization, visits, double-blind phase, open-label phase, safety assessments, treatment), with the only exception being the designation of the primary and secondary endpoints. Therefore, the predefined pooling of the results was justified and performed to provide a complete overview of between-group differences in efficacy, safety, and tolerability that may not have been evident in individual studies. The primary endpoint for the pooled analysis was mean change from baseline in frequency of headache days at 24 weeks. Secondary endpoints were mean change from baseline to week 24 in frequency of migraine/probable migraine days, frequency of moderate/severe headache days, total cumulative hours of headache on headache days, frequency of headache episodes, frequency of migraine/probable migraine episodes, frequency of acute headache pain medication intakes, and the proportion of patients with severe (> or =60) Headache Impact Test-6 score at week 24. Results of the pooled analyses of the 2 PREEMPT double-blind phases are presented. RESULTS: A total of 1384 adults were randomized to onabotulinumtoxinA (n = 688) or placebo (n = 696). Pooled analyses demonstrated a large mean decrease from baseline in frequency of headache days, with statistically significant between-group differences favoring onabotulinumtoxinA over placebo at week 24 (-8.4 vs -6.6; P < .001) and at all other time points. Significant differences favoring onabotulinumtoxinA were also observed for all secondary efficacy variables at all time points, with the exception of frequency of acute headache pain medication intakes. Adverse events occurred in 62.4% of onabotulinumtoxinA patients and 51.7% of placebo patients. Most patients reported adverse events that were mild to moderate in severity and few discontinued (onabotulinumtoxinA, 3.8%; placebo, 1.2%) due to adverse events. No unexpected treatment-related adverse events were identified. CONCLUSIONS: The pooled PREEMPT results demonstrate that onabotulinumtoxinA is an effective prophylactic treatment for chronic migraine. OnabotulinumtoxinA resulted in significant improvements compared with placebo in multiple headache symptom measures, and significantly reduced headache-related disability and improved functioning, vitality, and overall health-related quality of life. Repeat treatments with onabotulinumtoxinA were safe and well tolerated.

I. EXECUTIVE SUMMARY: BACKGROUND: The 5 years since the publication of the first International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR-RS) has witnessed foundational progress in our understanding and treatment of rhinologic disease. These advances are reflected within the more than 40 new topics covered within the ICAR-RS-2021 as well as updates to the original 140 topics. This executive summary consolidates the evidence-based findings of the document. METHODS: ICAR-RS presents over 180 topics in the forms of evidence-based reviews with recommendations (EBRRs), evidence-based reviews, and literature reviews. The highest grade structured recommendations of the EBRR sections are summarized in this executive summary. RESULTS: ICAR-RS-2021 covers 22 topics regarding the medical management of RS, which are grade A/B and are presented in the executive summary. Additionally, 4 topics regarding the surgical management of RS are grade A/B and are presented in the executive summary. Finally, a comprehensive evidence-based management algorithm is provided. CONCLUSION: This ICAR-RS-2021 executive summary provides a compilation of the evidence-based recommendations for medical and surgical treatment of the most common forms of RS.

BACKGROUND: Stimulating an immune response against cancer with the use of vaccines remains a challenge. We hypothesized that combining a melanoma vaccine with interleukin-2, an immune activating agent, could improve outcomes. In a previous phase 2 study, patients with metastatic melanoma receiving high-dose interleukin-2 plus the gp100:209-217(210M) peptide vaccine had a higher rate of response than the rate that is expected among patients who are treated with interleukin-2 alone. METHODS: We conducted a randomized, phase 3 trial involving 185 patients at 21 centers. Eligibility criteria included stage IV or locally advanced stage III cutaneous melanoma, expression of HLA*A0201, an absence of brain metastases, and suitability for high-dose interleukin-2 therapy. Patients were randomly assigned to receive interleukin-2 alone (720,000 IU per kilogram of body weight per dose) or gp100:209-217(210M) plus incomplete Freund's adjuvant (Montanide ISA-51) once per cycle, followed by interleukin-2. The primary end point was clinical response. Secondary end points included toxic effects and progression-free survival. RESULTS: The treatment groups were well balanced with respect to baseline characteristics and received a similar amount of interleukin-2 per cycle. The toxic effects were consistent with those expected with interleukin-2 therapy. The vaccine-interleukin-2 group, as compared with the interleukin-2-only group, had a significant improvement in centrally verified overall clinical response (16% vs. 6%, P=0.03), as well as longer progression-free survival (2.2 months; 95% confidence interval [CI], 1.7 to 3.9 vs. 1.6 months; 95% CI, 1.5 to 1.8; P=0.008). The median overall survival was also longer in the vaccine-interleukin-2 group than in the interleukin-2-only group (17.8 months; 95% CI, 11.9 to 25.8 vs. 11.1 months; 95% CI, 8.7 to 16.3; P=0.06). CONCLUSIONS: In patients with advanced melanoma, the response rate was higher and progression-free survival longer with vaccine and interleukin-2 than with interleukin-2 alone. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00019682.).

Renal cell carcinoma (RCC) is not a single disease, but several histologically defined cancers with different genetic drivers, clinical courses, and therapeutic responses. The current study evaluated 843 RCC from the three major histologic subtypes, including 488 clear cell RCC, 274 papillary RCC, and 81 chromophobe RCC. Comprehensive genomic and phenotypic analysis of the RCC subtypes reveals distinctive features of each subtype that provide the foundation for the development of subtype-specific therapeutic and management strategies for patients affected with these cancers. Somatic alteration of BAP1, PBRM1, and PTEN and altered metabolic pathways correlated with subtype-specific decreased survival, while CDKN2A alteration, increased DNA hypermethylation, and increases in the immune-related Th2 gene expression signature correlated with decreased survival within all major histologic subtypes. CIMP-RCC demonstrated an increased immune signature, and a uniform and distinct metabolic expression pattern identified a subset of metabolically divergent (MD) ChRCC that associated with extremely poor survival.

BACKGROUND: Fremanezumab, a humanized monoclonal antibody targeting calcitonin gene-related peptide (CGRP), is being investigated as a preventive treatment for migraine. We compared two fremanezumab dose regimens with placebo for the prevention of chronic migraine. METHODS: In this phase 3 trial, we randomly assigned patients with chronic migraine (defined as headache of any duration or severity on ≥15 days per month and migraine on ≥8 days per month) in a 1:1:1 ratio to receive fremanezumab quarterly (a single dose of 675 mg at baseline and placebo at weeks 4 and 8), fremanezumab monthly (675 mg at baseline and 225 mg at weeks 4 and 8), or matching placebo. Both fremanezumab and placebo were administered by means of subcutaneous injection. The primary end point was the mean change from baseline in the average number of headache days (defined as days in which headache pain lasted ≥4 consecutive hours and had a peak severity of at least a moderate level or days in which acute migraine-specific medication [triptans or ergots] was used to treat a headache of any severity or duration) per month during the 12 weeks after the first dose. RESULTS: Of 1130 patients enrolled, 376 were randomly assigned to fremanezumab quarterly, 379 to fremanezumab monthly, and 375 to placebo. The mean number of baseline headache days (as defined above) per month was 13.2, 12.8, and 13.3, respectively. The least-squares mean (±SE) reduction in the average number of headache days per month was 4.3±0.3 with fremanezumab quarterly, 4.6±0.3 with fremanezumab monthly, and 2.5±0.3 with placebo (P<0.001 for both comparisons with placebo). The percentage of patients with a reduction of at least 50% in the average number of headache days per month was 38% in the fremanezumab-quarterly group, 41% in the fremanezumab-monthly group, and 18% in the placebo group (P<0.001 for both comparisons with placebo). Abnormalities of hepatic function occurred in 5 patients in each fremanezumab group (1%) and 3 patients in the placebo group (<1%). CONCLUSIONS: Fremanezumab as a preventive treatment for chronic migraine resulted in a lower frequency of headache than placebo in this 12-week trial. Injection-site reactions to the drug were common. The long-term durability and safety of fremanezumab require further study. (Funded by Teva Pharmaceuticals; ClinicalTrials.gov number, NCT02621931 .).

BACKGROUND & AIMS: There are no effective and safe treatments for chronic hepatitis C virus (HCV) infection of patients who have advanced liver disease. METHODS: In this phase 2, open-label study, we assessed treatment with the NS5A inhibitor ledipasvir, the nucleotide polymerase inhibitor sofosbuvir, and ribavirin in patients infected with HCV genotypes 1 or 4. Cohort A enrolled patients with cirrhosis and moderate or severe hepatic impairment who had not undergone liver transplantation. Cohort B enrolled patients who had undergone liver transplantation: those without cirrhosis; those with cirrhosis and mild, moderate, or severe hepatic impairment; and those with fibrosing cholestatic hepatitis. Patients were assigned randomly (1:1) to receive 12 or 24 weeks of a fixed-dose combination tablet containing ledipasvir and sofosbuvir, once daily, plus ribavirin. The primary end point was sustained virologic response at 12 weeks after the end of treatment (SVR12). RESULTS: We enrolled 337 patients, 332 (99%) with HCV genotype 1 infection and 5 (1%) with HCV genotype 4 infection. In cohort A (nontransplant), SVR12 was achieved by 86%-89% of patients. In cohort B (transplant recipients), SVR12 was achieved by 96%-98% of patients without cirrhosis or with compensated cirrhosis, by 85%-88% of patients with moderate hepatic impairment, by 60%-75% of patients with severe hepatic impairment, and by all 6 patients with fibrosing cholestatic hepatitis. Response rates in the 12- and 24-week groups were similar. Thirteen patients (4%) discontinued the ledipasvir and sofosbuvir combination prematurely because of adverse events; 10 patients died, mainly from complications related to hepatic decompensation. CONCLUSION: The combination of ledipasvir, sofosbuvir, and ribavirin for 12 weeks produced high rates of SVR12 in patients with advanced liver disease, including those with decompensated cirrhosis before and after liver transplantation. ClinTrials.gov: NCT01938430.

(Cell Reports 23, 313–326; April 3, 2018) In the originally published version of this article, the author list contained two errors. Specifically, David J. Kwiatkowski was misspelled as David J. Kwaitkowski, and William Y. Kim was inadvertently written as William T. Kim. Both names have been corrected online. The authors regret this error. The Cancer Genome Atlas Comprehensive Molecular Characterization of Renal Cell CarcinomaRicketts et al.Cell ReportsApril 5, 2018In BriefRicketts et al. find distinctive features of each RCC subtype, providing the foundation for development of subtype-specific therapeutic and management strategies. Somatic alteration of BAP1, PBRM1, and metabolic pathways correlates with subtype-specific decreased survival, while CDKN2A alteration, DNA hypermethylation, and Th2 immune signature correlate with decreased survival within all subtypes. Full-Text PDF Open Access

BACKGROUND: Data regarding the efficacy of treatment with ibrutinib-rituximab, as compared with standard chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab, in patients with previously untreated chronic lymphocytic leukemia (CLL) have been limited. METHODS: In a phase 3 trial, we randomly assigned (in a 2:1 ratio) patients 70 years of age or younger with previously untreated CLL to receive either ibrutinib and rituximab for six cycles (after a single cycle of ibrutinib alone), followed by ibrutinib until disease progression, or six cycles of chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab. The primary end point was progression-free survival, and overall survival was a secondary end point. We report the results of a planned interim analysis. RESULTS: mutation was 87.7% in the ibrutinib-rituximab group and 88.0% in the chemoimmunotherapy group (hazard ratio for progression or death, 0.44; 95% CI, 0.14 to 1.36). The incidence of adverse events of grade 3 or higher (regardless of attribution) was similar in the two groups (in 282 of 352 patients [80.1%] who received ibrutinib-rituximab and in 126 of 158 [79.7%] who received chemoimmunotherapy), whereas infectious complications of grade 3 or higher were less common with ibrutinib-rituximab than with chemoimmunotherapy (in 37 patients [10.5%] vs. 32 [20.3%], P<0.001). CONCLUSIONS: The ibrutinib-rituximab regimen resulted in progression-free survival and overall survival that were superior to those with a standard chemoimmunotherapy regimen among patients 70 years of age or younger with previously untreated CLL. (Funded by the National Cancer Institute and Pharmacyclics; E1912 ClinicalTrials.gov number, NCT02048813.).

Supported by the American Association for the Study of Liver Diseases. Dr. Lai is partially supported by R01 AG059183 and R21 AG067554. Srinivasan Dasarathy is partially supported by NIH RO1 GM119174; RO1 DK113196; P50 AA024333; RO1 AA021890; 3U01AA026976 ‐ 03S1; UO1 AA 026976; R56HL141744;UO1 DK061732; 5U01 DK062470‐17S2. Potential conflict of interest: Dr. Lai received grants from Axcella and Lipocine. Dr. Bernal advises Versantis. Purpose and Scope of This Practice Guidance This is the first American Association for the Study of Liver Diseases (AASLD) practice guidance on the management of malnutrition, frailty, and sarcopenia in patients with cirrhosis. This guidance represents the consensus of a panel of experts after a thorough review and vigorous debate of the literature published to date, incorporating clinical experience and common sense to fill in the gaps when appropriate. Our goal was to offer clinicians pragmatic recommendations that could be implemented immediately in clinical practice to target malnutrition, frailty, and sarcopenia in this population. This AASLD guidance document differs from AASLD guidelines, which are supported by systematic reviews of the literature, formal rating of the quality of the evidence and strength of the recommendations, and, if appropriate, meta‐analysis of results using the Grading of Recommendations Assessment Development and Evaluation system. In contrast, this guidance was developed by consensus of an expert panel and provides guidance statements based on formal review and analysis of the literature on the topics, with oversight provided by the AASLD Practice Guidelines Committee at all stages of guidance development. The AASLD Practice Guidelines Committee chose to perform a guidance on this topic because a sufficient number of randomized controlled trials (RCTs) were not available to support the development of a guideline. Definitions of Malnutrition, Frailty, and Sarcopenia and Their Relationship in Patients With Cirrhosis Cirrhosis is a major predisposing condition for the development of malnutrition, frailty, and sarcopenia. Multiple, yet complementary, definitions of these conditions exist in the published domain outside of the field of hepatology; but consensus definitions have not yet been established by the AASLD for patients with cirrhosis. Furthermore, there has been ambiguity related to operationalization of these constructs in clinical practice. To address this, we offer definitions of the theoretical constructs of malnutrition, frailty, and sarcopenia as commonly represented in all populations, partnered with operational definitions, developed by consensus, to facilitate pragmatic implementation of these constructs in clinical practice as applied to patients with cirrhosis (Table 1). Malnutrition is a clinical syndrome that results from “an imbalance (deficiency or excess) of nutrients that causes measurable adverse effects on tissue/body form (body shape, size, composition) or function, and/or clinical outcome.”(1) Key to this definition is the recognition that malnutrition represents a spectrum of nutritional disorders across the entire range of body mass index (BMI)—from underweight to obese. By this definition, malnutrition leads to adverse physical effects, which, in patients with cirrhosis, are commonly manifested phenotypically as frailty or sarcopenia. Frailty has most commonly been defined as a clinical state of decreased physiologic reserve and increased vulnerability to health stressors, a definition that has its roots in the field of geriatrics.(2) However, the weight of evidence available to date in patients with cirrhosis has focused predominantly on one component of frailty: physical frailty. Although this representation deviates somewhat from the classic “geriatric” definition of frailty as a global construct, physical frailty represents clinical manifestations of impaired muscle contractile function that are commonly reported by patients with cirrhosis such as decreased physical function, decreased functional performance, and disability. Sarcopenia has been defined by the European Working Group on Sarcopenia as “a progressive and generalized skeletal muscle disorder associated with an increased likelihood of adverse outcomes including falls, fractures, disability, and mortality,” combining both muscle mass and muscle strength or muscle performance in its definition.(3) However, the majority of studies in patients with cirrhosis have investigated sarcopenia using measures of muscle mass alone. Therefore, based on the evidence available to date on patients with cirrhosis, we have developed a consensus definition for operationalization of sarcopenia in patients with cirrhosis as the phenotypic manifestation of loss of muscle mass. Table 1 - Definitions for the Theoretical Constructs of Malnutrition, Frailty, and Sarcopenia and Consensus‐Derived Operational Definitions Applied to Patients with Cirrhosis Construct Theoretical Definitions Operational Definitions Malnutrition A clinical syndrome that results from deficiencies or excesses of nutrient intake, imbalance of essential nutrients, or impaired nutrient use( 4 ) An imbalance (deficiency or excess) of nutrients that causes measurable adverse effects on tissue/body form (body shape, size, composition) or function and/or clinical outcome( 1 ) Frailty A clinical state of decreased physiologic reserve and increased vulnerability to health stressors( 2 ) The phenotypic representation of impaired muscle contractile function Sarcopenia A progressive and generalized skeletal muscle disorder associated with an increased likelihood of adverse outcomes including falls, fractures, disability, and mortality( 3 ) The phenotypic representation of loss of muscle mass Although we have, for the purposes of this guidance, developed separate operational definitions for malnutrition, frailty, and sarcopenia, we acknowledge that these three constructs are interrelated and in practice are often recognized simultaneously in an individual patient. For example, a patient with cirrhosis who presents to clinic with severe muscle wasting might be described as “malnourished,” “frail,” and “sarcopenic,” each descriptor conveying similar information about the patient’s poor clinical condition and prognosis. Despite the overlap of these three constructs in clinical practice, there is value in understanding each as a separate entity as well as the relationship the three in to and for these we a for this relationship 1). are a number of that to malnutrition in patients with cirrhosis, which is to at the phenotypically as frailty and/or sarcopenia. Malnutrition is not the that to frailty and such as cirrhosis physical and to frailty and/or sarcopenia or of the malnutrition In frailty and sarcopenia to each muscle contractile function loss of muscle mass and is these clinical and to adverse health outcomes including increased health quality of adverse and increased of to malnutrition, frailty, and sarcopenia and the relationship these three and with physical and to leads to frailty and sarcopenia. to frailty and sarcopenia of to Frailty and Sarcopenia in Patients With Cirrhosis we the that have been to to frailty and sarcopenia in patients with cirrhosis. acknowledge that these in but for the purposes of of clinical we have these as malnutrition, physical and Malnutrition of results from including and or impaired of and to and is a of and is by a of and patients with cirrhosis have about including and or the spectrum of nutritional disorders from to of leads to of in patients with cirrhosis. to impaired and to of In and deficiencies have been reported in patients with and deficiencies have been well in patients with of these have a with frailty or sarcopenia. is associated with impaired muscle contractile function in the Although studies the of on frailty and sarcopenia in patients with cirrhosis are is in patients with and to the development and of frailty in this population. of a in the that is associated with frailty, and sarcopenia in patients with because of of in the and is by is associated with performance as well as muscle strength in with and with increased in with nutrient is from and leads to in the of and of This in and of as well as impaired and of and in both and to and in patients with cirrhosis and or as a of and the an from to and increased of has been defined in the literature 1 or With its associated to the imbalance and in at of patients with cirrhosis a of with or Cirrhosis leads to frailty and sarcopenia a number of the the state in cirrhosis leads to an imbalance and of that are essential for and results in of which leads to muscle from loss of in with increased with effects on the is that decreased increased and in the skeletal of contractile with in muscle contractile and loss of muscle The of has been associated with in the of For example, has been associated with a of sarcopenia, of patients with sarcopenia was reported in of patients with cirrhosis from and Patients with cirrhosis the most of in muscle with muscle and the Patients with cirrhosis to be at increased of sarcopenia to the effects of and such as to that skeletal muscle the 1 that is in of to malnutrition and muscle is associated with physical and to increased and physical and are associated with and of such as and are in patients with from increased from impaired of and and from in the This the development of frailty, sarcopenia, and muscle and increased in the of cirrhosis, to and vulnerability to frailty and sarcopenia. are in of with results in a of these and are by of of the from in of and in and have been in patients with cirrhosis and sarcopenia with patients who are in in body the of in the development and of sarcopenia. has been associated with frailty and sarcopenia in patients with cirrhosis and is of the of is associated with and A has been and muscle loss in patients with cirrhosis, with one of patients with and cirrhosis for sarcopenia by skeletal muscle index With to muscle function, has not been associated with an increased of frailty, one of patients with cirrhosis a and frailty on clinical patients with a who were a increased of with patients who were with the there has been a in the of cirrhosis in In with cirrhosis, a of and sarcopenia simultaneously and has been to as In sarcopenia was associated with of and patients with cirrhosis but and are common in patients with cirrhosis and are associated with frailty and sarcopenia as well as In one of of in and a of was who in who outcomes on the for or In a of and of patients and reported that clinicians that one to in physical is the the of physical are studies the of physical on progressive frailty and/or sarcopenia. However, a number of trials have a of to physical with nutritional on muscle function, muscle and functional studies that physical in to in muscle function and/or muscle mass. of of we and a in the development of malnutrition, frailty, and sarcopenia. is by and is associated with physical frailty to such as or to is associated with in patients with in the in for physical and management of cirrhosis for increased patient and of patients with cirrhosis and the to and management of cirrhosis that to at the and the development of malnutrition, frailty, and sarcopenia in this population. to to the development of all of these including in and adverse In an of has been to be associated with the of patients with cirrhosis, there be clinical to to and to target the Although a or a with in patients with is health not offer this or for to for to Furthermore, there be about which is for management the of a of Frailty and Sarcopenia Frailty Assessment of Frailty in and to frailty as a global or its individual physical frailty, disability, functional that have been in or with cirrhosis are in Table The are in the from by the or to The majority of these have been in the the “geriatric” of frailty as a state of decreased physiologic However, the value of the that have been in the of and the pragmatic for to the effects of frailty and sarcopenia in patients with cirrhosis Table 2 - to Frailty or Frailty that have been in Patients with Cirrhosis of Frailty Frailty ) frailty using on a of 1 and ) to to function or or with that are essential to function ) to or functional from evidence of to and to ) in in for to from to of the but in all and to not ) to or functional 2 in the and 4 Frailty ) frailty of weight loss and physical Frailty ) frailty for with of weight loss and physical ) frailty The patient is to a using the with The is 3 and the are ) of the of the ) and on a at ) physical function of three and three for each Liver Frailty ) frailty of and in Liver Frailty are associated with ) of functional of at and to both and have to the of frailty. patients be as or performance using of or The Liver Frailty has established to Frailty Frailty and Frailty performance to a of functional The that have the and outcomes in patients with cirrhosis are the and the Liver Frailty to frailty in the for of frailty in are to the for in the by or by and of and However, a studies have that the of frailty has to with The frailty developed in and in patients with cirrhosis of all has been for Although of frailty was in this of of the majority of are to the Frailty the to an frailty for 2 of is the a of global functional developed for with which be by the or clinical in the of muscle contractile function 1 of and Frailty is common patients with its with of frailty in this have because of the of a number of to impaired muscle contractile patients with cirrhosis in the the reported of frailty has from to patients with cirrhosis, the of frailty is as as for with for when as using the of frailty have been reported to be as as when as impaired performance using the the Frailty of with the for frailty, with as as with Frailty in the majority of patients with cirrhosis patients in the or at experience in with a of by 1 Frailty, as by the Liver Frailty in of patients with cirrhosis a of on the and after Liver Frailty from in and of of patients functional as defined by a Liver Frailty of by 1 after Association With Frailty has been with in both the and as well as the For example, frailty, by the Liver Frailty was associated with a increased of in a of patients with cirrhosis at In including patients with cirrhosis, disability, as by the for with three or was associated with a increased of In the functional performance, by the was associated with for after for in frailty and of patients with cirrhosis at each in the Liver Frailty 3 was associated with a increased of of frailty and for Liver of at were who severe with who Although this was a is that who frailty a of of the of frailty to in this frailty measures have been with outcomes outcomes of health in both patients health of physical function after and patients of to a Furthermore, frailty is associated with including development of falls, disability, and global quality of Guidance 1 patients with cirrhosis be for frailty with a both at and are to the of one frailty we that of the frailty in clinical practice the for of that clinical In patients with cirrhosis, frailty be patients with cirrhosis from 2 patients with cirrhosis be on the and adverse clinical of frailty of frailty Sarcopenia Assessment of Sarcopenia in and to muscle mass in patients with cirrhosis are in Table Table 3 - to that have been in Patients with Liver ) by with and and for patient but poor and with ) and ) to nutritional and the in patients with the of body mass using in patients with ) in patients with of of with and of are to to for ) analysis measures muscle and quality and mass has been defined by muscle ) and in patients with cirrhosis mass with ) analysis measures muscle and a of to not available at of not quality of the most evidence to support its but has with and mass measures that have been muscle index skeletal muscle ) and with is the for of muscle mass in cirrhosis, but and to of for the of sarcopenia in clinical However, when is for clinical as in patients with or for mass be from clinical using available mass is reported as the as the skeletal muscle at to muscle has been in patients with cirrhosis with muscle as muscle to but has been to be with body as by skeletal muscle Furthermore, muscle index to of in patients with cirrhosis when with by is well in patients with cirrhosis but the theoretical as measures of muscle mass is often and available in of muscle mass have been in patients with cirrhosis. Assessment of mass by analysis including has been to with muscle mass and is associated with in patients with the of body mass by have in patients with cirrhosis, with of for clinical practice is of the of measures of body to muscle such as or be available in practice but have in patients with cirrhosis to in body in are to and the to body which is of of in with Sarcopenia is in the because muscle contractile function be to in of muscle mass an of because measures such as and such as are often by and This is in for the value of to with provides the most of muscle with the of muscle skeletal muscle including for including of are the with development in Sarcopenia is common in with cirrhosis, of patients with to the there are in the of sarcopenia, with of and of with cirrhosis for sarcopenia by in one The of muscle loss with of in but not In sarcopenia has been reported in of with Association With sarcopenia in patients with cirrhosis have focused on muscle mass in the Sarcopenia has been to be a of a spectrum of outcomes in with cirrhosis both with and outcomes have not both and after but quality of increased of and In a meta‐analysis of across studies in published and as defined by a range of skeletal muscle mass was associated with a of for and for A separate American of patients with cirrhosis for to in and in were in a separate of all Although the of patients with in the at in predominantly of and in is to the value of across all studies to date have a of sarcopenia, but that sarcopenia is progressive and that measures of of muscle loss from measures are of clinical In with sarcopenia has been associated with adverse outcomes including and to the state of decreased muscle mass in the of increased mass. This presents a clinical in that be to because mass muscle The of in patients with cirrhosis from to has been to be a for after for defined as and is an for in patients with of are to as cirrhosis related to Guidance 3 the and muscle mass and outcomes in both and with cirrhosis, measures of muscle loss be to for poor outcomes in patients with cirrhosis. 4 as by analysis is as the most and to muscle mass in patients with cirrhosis. are to support a to muscle mass in patients with cirrhosis. of skeletal muscle mass has not been in patients with cirrhosis but provides the information on muscle mass as of the of to of for the of muscle mass is not for but of skeletal muscle mass be when an is as of clinical or in patients in of muscle contractile function is not or for Frailty and Sarcopenia in and of muscle by have the of and measures of muscle However, the of sarcopenia in patients with cirrhosis, its clinical is by the of and available for the to frailty be in the and at and, most be at Furthermore, measures of muscle contractile function be associated measures of muscle with outcomes including and the to For the purposes of clinical practice, one not The of to frailty or sarcopenia on the clinical and the and of frailty we of frailty using a which there are to (Table all patients with cirrhosis. Assessment of muscle on the be in in measures of frailty are or who often perform of muscle contractile In this muscle mass be an of physiologic reserve and for of the patient’s with in of muscle mass be measures of muscle contractile function the of in For the purposes of frailty and sarcopenia and because are and of outcomes in patients with cirrhosis. that the of sarcopenia in patients with cirrhosis is sarcopenia offer for development. In of muscle mass not patient and be as a in patients who are and on However, frailty has the of an individual and with the individual frailty be a of a patient’s quality of sarcopenia. For these we the of both frailty and sarcopenia as in Guidance In clinical we systematic of frailty and/or sarcopenia in all patients with cirrhosis using a Frailty be in the and when and are to or to Sarcopenia be for patients in of of frailty is not or is because of severe or to in such as in In studies of patients with cirrhosis, including clinical trials related to malnutrition and/or muscle we of both frailty and sarcopenia, when to the of on these for the of Malnutrition, Frailty, and Sarcopenia in Practice all patients with cirrhosis to muscle mass and contractile function on of cirrhosis, but we that this is not in most clinical In an to the to with the we have recommendations a classic for and health with each at stages of of and to to patients with sarcopenia or frailty. to the of in patients with sarcopenia or frailty. to the of in patients with sarcopenia or frailty not to The goal is to the of adverse health outcomes to malnutrition, frailty, and The three of and health as applied to management of malnutrition, frailty, and sarcopenia in patients with this we have developed a clinical practice for and management of malnutrition, frailty, and sarcopenia in patients with cirrhosis Key to this is the of of malnutrition frailty, and be for the development or for of these Although for have not been established in the literature, there are three that have recommendations for of frailty and sarcopenia with patients with cirrhosis be with cirrhosis. clinical trials of that target muscle such as nutritional or outcomes at but as as and the of Frailty and Sarcopenia consensus on frailty and management in for frailty the on an on these we that of malnutrition to the for Malnutrition frailty, and sarcopenia at for patients with but as as with cirrhosis and/or management for malnutrition, frailty, and for and management of malnutrition, frailty, and sarcopenia in patients with patients with cirrhosis and support to of these conditions A frailty or sarcopenia for and the development of an management of frailty or sarcopenia using the as at for patients with but as as for with cirrhosis and/or management for these Patients with progressive frailty or sarcopenia of and the of a and a of the patient’s and health there is a health when However, if not available at all of at a to a and is at the a of the patient’s and health with in patients with including be with each of but this not be in practice a a patient be to a and a if malnutrition, frailty, and/or sarcopenia are progressive and the of malnutrition, frailty, and sarcopenia in patients with cirrhosis, that target one condition the conditions as we pragmatic guidance for the management of malnutrition, frailty, and sarcopenia in patients with cirrhosis This information was for who are not in or to in and and management with to facilitate and management of malnutrition, frailty, and sarcopenia in patients with for Malnutrition to for malnutrition have been in patients with the has been the most associated with a of Patients are three nutritional and based on a of of or for nutritional weight or of nutritional and with to Patients at for malnutrition based on the have been to experience clinical outcomes including function, and quality of in the has been associated with the of be of is associated with a in of with in who are not with skeletal be partially with Although the with sarcopenia and are not well the of and to both and that have the to muscle of A theoretical for the management of frailty and sarcopenia with that or its In an of and and muscle and muscle mass and the that to have a in and of sarcopenia as However, the of management on muscle contractile function or muscle mass in patients with cirrhosis are a in a impaired by and to function and In of was associated with of a of muscle of sarcopenia, and increased of physical However, a systematic review not of for the of its for the management of frailty and/or sarcopenia in clinical practice be of of be as and to and In intake, and as well as of in patients with cirrhosis and has been associated with loss of muscle this is to one and has not been in its be the of controlled for of of a in patients with has been associated with in body with of body and an in and muscle However, to muscle mass after is in to one of patients and is associated with increased sarcopenia is a for to muscle mass after is evidence the of for the management of frailty and/or sarcopenia, for offer to the patient in the form of in muscle mass. Liver for of Liver is associated with of frailty and sarcopenia in but not and often not to of and In a that the of patients who were Frailty decreased from to at after but for by a Liver Frailty of were related to the of a both for to or frailty and for to and patients With to sarcopenia, separate studies including and of in muscle mass and after one of the studies that developed sarcopenia after but not of muscle to recommendations offer to frailty and/or sarcopenia in but be for the of these Although frailty and/or sarcopenia after in both frailty and sarcopenia are associated with adverse including after the of frailty or sarcopenia in the of a patient’s for we the of for frailty and/or sarcopenia for However, in the of of of frailty or sarcopenia that of with we not using frailty or sarcopenia as Guidance of conditions that to cirrhosis, such as and is to malnutrition, frailty, and sarcopenia. and management of is in all patients with cirrhosis to malnutrition, frailty, and sarcopenia. for offer an of muscle mass. In the of on which patients experience in frailty and sarcopenia be for the of frailty or sarcopenia. not using frailty or sarcopenia as an A be provided to all patients with cirrhosis that is to nutritional a patient who for frailty or sarcopenia nutritional support to a patient who not these for of nutritional be at with for for frailty or sarcopenia at and/or of muscle contractile function or mass. clinical or of target and intake, causes be and the Guidance patients with cirrhosis of a of and the nutritional and outcomes and to nutritional Patients with cirrhosis who for malnutrition frailty, or sarcopenia a that is to and individual of the most of a is to the patient’s using a is the for but is not available in all practice of a to has been in patients with cirrhosis to and be at the with in on the of In the of be to an but there is in of in patients with cirrhosis have that from to on these for patients with and/or cirrhosis a of at In patients with weight be using based on weight or a of weight based on the of with to the Although are on patients with cirrhosis across the spectrum of there is of the for In of this,

PURPOSE BRCA1 or BRCA2 ( BRCA) alterations are common in men with metastatic castration-resistant prostate cancer (mCRPC) and may confer sensitivity to poly(ADP-ribose) polymerase inhibitors. We present results from patients with mCRPC associated with a BRCA alteration treated with rucaparib 600 mg twice daily in the phase II TRITON2 study. METHODS We enrolled patients who progressed after one to two lines of next-generation androgen receptor–directed therapy and one taxane-based chemotherapy for mCRPC. Efficacy and safety populations included patients with a deleterious BRCA alteration who received ≥ 1 dose of rucaparib. Key efficacy end points were objective response rate (ORR; per RECIST/Prostate Cancer Clinical Trials Working Group 3 in patients with measurable disease as assessed by blinded, independent radiology review and by investigators) and locally assessed prostate-specific antigen (PSA) response (≥ 50% decrease from baseline) rate. RESULTS Efficacy and safety populations included 115 patients with a BRCA alteration with or without measurable disease. Confirmed ORRs per independent radiology review and investigator assessment were 43.5% (95% CI, 31.0% to 56.7%; 27 of 62 patients) and 50.8% (95% CI, 38.1% to 63.4%; 33 of 65 patients), respectively. The confirmed PSA response rate was 54.8% (95% CI, 45.2% to 64.1%; 63 of 115 patients). ORRs were similar for patients with a germline or somatic BRCA alteration and for patients with a BRCA1 or BRCA2 alteration, while a higher PSA response rate was observed in patients with a BRCA2 alteration. The most frequent grade ≥ 3 treatment-emergent adverse event was anemia (25.2%; 29 of 115 patients). CONCLUSION Rucaparib has antitumor activity in patients with mCRPC and a deleterious BRCA alteration, but with a manageable safety profile consistent with that reported in other solid tumor types.

BACKGROUND: Septic shock is associated with vasopressin deficiency and a hypersensitivity to its exogenous administration. The goal of the current study was to determine whether short-term vasopressin infusion in patients experiencing severe septic shock has a vasopressor sparing effect while maintaining hemodynamic stability and adequate end-organ perfusion. METHODS: Patients experiencing septic shock that required high-dose vasopressor support were randomized to a double-blinded 4-h infusion of either norepinephrine (n = 11) or vasopressin (n = 13), and open-label vasopressors were titrated to maintain blood pressure. To assess end-organ perfusion, urine output and creatinine clearance, gastric mucosal carbon dioxide tension, and electrocardiogram ST segment position were measured. RESULTS: Patients randomized to norepinephrine went from a median prestudy norepinephrine infusion of 20.0 microg/min to a blinded infusion of 17.0 mug/min at 4 h, whereas those randomized to vasopressin went from a median prestudy norepinephrine infusion of 25.0 microg/min to 5.3 microg/min at 4 h (P < 0.001). Mean arterial pressure and cardiac index were maintained in both groups. Urine output did not change in the norepinephrine group (median, 25 to 15 ml/h) but increased substantially in the vasopressin group (median, 32.5 to 65 ml/h; P < 0.05). Similarly, creatinine clearance did not change in the norepinephrine group but increased by 75% in the vasopressin group (P < 0.05). Gastric mucosal carbon dioxide tension and electrocardiogram ST segments did not change significantly in either group. CONCLUSIONS: The authors conclude that short-term vasopressin infusion spared conventional vasopressor use and improved some measures of renal function in patients with severe septic shock.

BACKGROUND: Selinexor, a selective inhibitor of nuclear export compound that blocks exportin 1 (XPO1) and forces nuclear accumulation and activation of tumor suppressor proteins, inhibits nuclear factor κB, and reduces oncoprotein messenger RNA translation, is a potential novel treatment for myeloma that is refractory to current therapeutic options. METHODS: We administered oral selinexor (80 mg) plus dexamethasone (20 mg) twice weekly to patients with myeloma who had previous exposure to bortezomib, carfilzomib, lenalidomide, pomalidomide, daratumumab, and an alkylating agent and had disease refractory to at least one proteasome inhibitor, one immunomodulatory agent, and daratumumab (triple-class refractory). The primary end point was overall response, defined as a partial response or better, with response assessed by an independent review committee. Clinical benefit, defined as a minimal response or better, was a secondary end point. RESULTS: A total of 122 patients in the United States and Europe were included in the modified intention-to-treat population (primary analysis), and 123 were included in the safety population. The median age was 65 years, and the median number of previous regimens was 7; a total of 53% of the patients had high-risk cytogenetic abnormalities. A partial response or better was observed in 26% of patients (95% confidence interval, 19 to 35), including two stringent complete responses; 39% of patients had a minimal response or better. The median duration of response was 4.4 months, median progression-free survival was 3.7 months, and median overall survival was 8.6 months. Fatigue, nausea, and decreased appetite were common and were typically grade 1 or 2 (grade 3 events were noted in up to 25% of patients, and no grade 4 events were reported). Thrombocytopenia occurred in 73% of the patients (grade 3 in 25% and grade 4 in 33%). Thrombocytopenia led to bleeding events of grade 3 or higher in 6 patients. CONCLUSIONS: Selinexor-dexamethasone resulted in objective treatment responses in patients with myeloma refractory to currently available therapies. (Funded by Karyopharm Therapeutics; STORM ClinicalTrials.gov number, NCT02336815.).