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Katerina Zakka,1 Renjian Jiang,2 Olatunji B Alese,1 Walid L Shaib,1 Christina Wu,1 Joel P Wedd,3 Marty T Sellers,4 Madhusmita Behera1,2 Bassel F El-Rayes,1 Mehmet Akce11Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA; 2Department of Research Informatics, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA; 3Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA; 4Division of General and GI Surgery, Department of Surgery, Emory University School of Medicine, Atlanta, GA, USABackground: HCC variants are rare primary hepatic tumors. The aim of this study is to compare clinical characteristics and outcomes of HCC variants with pure HCC.Methods: Patients diagnosed between 2004 and 2013 with ICD-O-3 8180/3 and 8170/3-8175/3 were identified from the National Cancer Database. Univariate and multivariate survival analyses were conducted to analyze the association between histology and overall survival (OS).Results: 80,280 patients were identified; pure HCC 78,461 (97.7%), fibrolamellar (FLHCC) 310 (0.4%), scirrhous 161 (0.2%), spindle cell 72 (0.1%), clear cell 487 (0.6%), pleomorphic 23 (0.0%), and combined HCC and cholangiocarcinoma (mixed HCC) 766 (1.0%). 76.7% were male and 72% Caucasian. Liver transplant was performed in 10.1% of pure HCC, 14.5% of mixed HCC, 16.2% of scirrhous, 6.9% of spindle cell, 8.8% of clear cell, 8.7% of pleomorphic, and 3.2% of FLHCC (p

Background and Objective: Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related deaths, and case numbers continue to rise in the United States. HCC carries a poor prognosis, and management requires a multidisciplinary approach. This narrative review aims to identify opportunities for further integration of palliative care (PC) in HCC care. Given the high symptom burden faced by patients with HCC, early PC consultation can be beneficial for patients., Methods: A search of PubMed was conducted from inception of the database to March 1, 2023. The search was composed of keywords and controlled vocabulary terms for concepts related to palliative medicine and symptom management in the setting of HCC., Key Content and Findings: This narrative review finds that although PC has been integrated into HCC guidelines, partnerships between PC and hepatology are still nascent in clinical practice. Treatment-related barriers pose a challenge to timely integration of PC in the care of HCC patients; evaluation or listing for transplantation can be perceived as a barrier to PC consultation, and unpredictable clinical courses make prognostication challenging. Providers may hesitate to pursue PC referral due to a lack of consensus around the role of PC, and for those that are referred, timing of consultation remains an issue, especially for those who are potential liver transplant candidates. There are few studies of PC in HCC, limiting evidence-based recommendations that can be made regarding PC involvement in this patient population., Conclusions: While PC is not routinely integrated into HCC care, recent guideline recommendations and a growing number of studies may change this over time. Although further evidence is needed, PC and hepatology teams partnering together can explore ways to improve the care of this patient population. PC consultation early in HCC care could assist in management of symptom relief, psychosocial and spiritual support, and caregiver support. Effective communication will be required to set parameters for referral and clarify potential outcomes of consultation. Teams should be prepared for the challenges involved in a culture change and paradigm shift in clinical practice.

Objective: To investigate the optimal timing of direct acting antiviral (DAA) administration in patients with hepatitis C-associated hepatocellular carcinoma (HCC) undergoing liver transplantation (LT)., Summary of Background Data: In patients with hepatitis C (HCV) associated HCC undergoing LT, the optimal timing of direct-acting antivirals (DAA) administration to achieve sustained virologic response (SVR) and improved oncologic outcomes remains a topic of much debate., Methods: The United States HCC LT Consortium (2015-2019) was reviewed for patients with primary HCV-associated HCC who underwent LT and received DAA therapy at 20 institutions. Primary outcomes were SVR and HCC recurrence-free survival (RFS)., Results: Of 857 patients, 725 were within Milan criteria. SVR was associated with improved 5-year RFS (92% vs 77%, P < 0.01). Patients who received DAAs pre-LT, 0-3 months post-LT, and ≥3 months post-LT had SVR rates of 91%, 92%, and 82%, and 5-year RFS of 93%, 94%, and 87%, respectively. Among 427 HCV treatment-naïve patients (no previous interferon therapy), patients who achieved SVR with DAAs had improved 5-year RFS (93% vs 76%, P < 0.01). Patients who received DAAs pre-LT, 0-3 months post-LT, and ≥3 months post-LT had SVR rates of 91%, 93%, and 78% (P < 0.01) and 5-year RFS of 93%, 100%, and 83% (P = 0.01)., Conclusions: The optimal timing of DAA therapy appears to be 0 to 3 months after LT for HCV-associated HCC, given increased rates of SVR and improved RFS. Delayed administration after transplant should be avoided. A prospective randomized controlled trial is warranted to validate these results., Competing Interests: S. A. Shah, Veloxis Pharmaceuticals Role(s): Membership on advisory committee or review panels. Organ Recovery Systems Role(s): Other activities (please specify), Research funding. J. Emamaullee, iSPY COVID trial Role(s): Other activities (please specify), Data Monitoring Committee. Gilead Role(s): Other activities (please specify), Research funding. American Society of Transplant Surgeons Role(s): Other activities (please specify), Research funding. American Association for the Study of Liver Diseases Role(s): Other activities (please specify), Research Funding. National Cancer Institute Role(s): Other activities (please specify), Research funding. M. H. Nguyen, Gilead Role(s): Other activities (please specify), Research support. Glycotest Role(s): Other activities (please specify), Research support. National Cancer Institute Role(s): Other activities (please specify), Research support. Bayer Role(s): Consulting. Esai Role(s): Consulting. Novartis Role(s): Consulting. Gilead Role(s): Consulting. Exact Sciences Role(s): Consulting. Laboratory of Advanced Medicine Role(s): Consulting. W. C. Chapman, Novartis Role(s): Membership on advisory committee or review panels. Pathfinder Role(s): Other activities (please specify), IP royalties.; S. K. Maithel, Celgene (Bristol Meyers Squibbs). All the other authors report no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Sarcopenia and inflammation are independently associated with worse survival in cancer patients. This study aims to determine the impact of sarcopenia, body mass index (BMI), and inflammatory biomarkers on survival in advanced hepatocellular carcinoma (HCC) patients treated with anti-PD-1 antibody-based immunotherapy., Methods: A retrospective review of advanced HCC patients treated with immunotherapy at Winship Cancer Institute between 2015 and 2019 was performed. Baseline computed tomography and magnetic resonance images were collected at mid-L3 level, assessed for skeletal muscle density using SliceOmatic (TomoVision, version 5.0) and converted to skeletal muscle index (SMI) by dividing it by height (m2). Sex-specific sarcopenia was defined by the median value of SMI. The optimal cut for continuous inflammation biomarker was determined by bias-adjusted log-rank test. Overall survival (OS) was set as primary outcome and Cox proportional hazard model was used for association with survival., Results: A total of 57 patients were included; 77.2% male, 52.6% Caucasian, 58.5% Eastern Cooperative Oncology Group performance status 0-1, 80.7% Child Pugh A. Treatment was second line and beyond in 71.9% of patients. The median follow-up time was 6 months. Sarcopenia cut-off for males and females was SMI of 43 and 39, respectively. 49.1% of patients had sarcopenia. Median OS was 5 versus 14.3 months in sarcopenic versus nonsarcopenic patients (Log-rank P=0.054). Median OS was 5 and 17.5 months in patients with BMI <25 and BMI ≥25, respectively (Log-rank P=0.034). Median OS was 3.6 and 14.3 months for patients with neutrophil-to-lymphocyte ratio (NLR) ≥5.15 versus NLR <5.15 (Log-rank P<0.001). In multivariable Cox regression model, higher baseline NLR was associated with worse OS (hazard ratio [HR]: 4.17, 95% confidence interval [CI]: 1.52-11.39, P=0.005). Sex-specific sarcopenia showed a trend of worse OS (HR: 1.71, 95% CI: 0.73-4.00, P=0.215) but was not statistically significant. BMI<25 was associated with worse OS (HR: 2.28, 95% CI: 0.92-5.65, P=0.076). In the association with progression free survival, neither baseline BMI nor sex-specific sarcopenia showed statistical significance., Conclusion: After controlling for baseline Child Pugh score and NLR, sex-specific sarcopenia does not predict OS. Baseline BMI and NLR together may predict OS in advanced HCC patients treated with anti-PD-1 antibody., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer related mortality worldwide, with the most common underlying etiologies being chronic hepatitis B and hepatitis C infections. Treatment of these viral hepatidities in the setting of HCC has been debated, and there is increasing study addressing this topic. Patients with advanced HCC of either etiology are unlikely to benefit from antiviral treatments, and futility should be considered prior to starting antiviral therapy. Hepatitis B treatment has demonstrated improved survival, decreased risk of hepatitis B reactivation, and decreased risk of late HCC recurrence. The mainstay treatment of chronic hepatitis B has been nucleos(t)ide analogues (NAs), and in the setting of HCC, entecavir and tenofovir are preferred given their higher potency and barriers to resistance. Those who were already on a NAs at the time of HCC diagnosis should be continued on them regardless of the HCC management planned. Patients who are suitable candidates to start NAs should start them at the time of HCC diagnosis. Direct-acting antivirals (DAAs) are the first line therapies for hepatitis C. Unlike with hepatitis B, those with HCV-associated HCC are recommended to start treatment 3-6 months after complete treatment of their HCC, given lower rates of sustained virologic response (SVR) with active HCC. There are also controversial concerns about DAAs contributing to a more aggressive HCC phenotype, but data are limited by retrospective studies, and more recent retrospective studies are more reassuring. In transplant candidates, starting DAAs may be deferred until after transplant depending on median regional wait times, availability of HCV positive organs, and the degree of the patient's liver dysfunction. Overall, in patients with HCC from hepatitis B or C, treatment of the underlying viral hepatitis should be considered unless advanced stage limits benefits and results in futility.

Generalized lymphadenopathy after organ transplant is a concerning finding, often indicating the devel-opment of lymphoma. We describe a 52-year-old liver transplant recipient who had clinical symptoms and imaging concerning for posttransplant lymphoproliferative disease. However, histologic evaluation of a lymph node biopsy revealed that the patient actually had a much rarer but relatively benign condition, Kikuchi-Fujimoto disease (histiocytic necrotizing lymphadenitis). We discuss the epidemiology, clinical symptoms, diagnosis, histologic features, and treatment of this uncommon mimic of posttransplant lymphoproliferative disease.

Background: Ledipasvir and sofosbuvir is a well-tolerated regimen with high sustained virological response (SVR) rates in pre-liver transplant patients infected with chronic hepatitis C virus (HCV), but data in liver transplant recipients outside of clinical trials is limited., Aim: To address this knowledge gap and assess SVR rates without the use of ribavirin in liver transplant recipients METHODS: This is a retrospective study examining the treatment of 75 post-liver transplant recipients with ledipasvir and sofosbuvir without ribavirin. Differences between SVR cohorts and predictors of SVR were analysed in an intention-to-treat (ITT) fashion., Results: A total of 408 genotype 1, HCV patients were treated with ledipasvir/sofosbuvir from October 2014 to August 2015 at our centre. Seventy-three patients were post-liver transplant and were treated with a median of 2.9 years from transplant. Ledipasvir/sofosbuvir achieved an SVR12 of 95.9%. African Americans made up 28.8% of the cohort. Sixty-three per cent of patients were treated previously, including 13.7% of patients previously treated with direct-acting antivirals. Only 2.7% had recurrent allograft cirrhosis, and the majority (90.4%) was on calcineurin inhibitor based immunosuppressive therapy. Approximately 82% of patients had chronic kidney disease (CKD) stage 2 or 3. In univariate logistic regression, only detectable week 8 viral load was predictive of failure to achieve SVR., Conclusion: Our data confirm excellent SVR outcomes and favourable safety and tolerability profiles with ledipasvir/sofosbuvir without ribavirin in post-liver transplant recipients infected with HCV, despite treatment guidelines to use ribavirin., (© 2017 John Wiley & Sons Ltd.)

The Model for End-Stage Liver Disease (MELD) score has reduced accuracy for liver transplantation (LT) wait-list mortality when MELD ≤ 20. Neutrophil-to-lymphocyte ratio (NLR) is a biomarker associated with systemic inflammation and may predict cirrhotic decompensation and death. We aimed to evaluate the prognostic utility of high NLR (≥4) for liver-related death among low MELD patients listed for LT, controlling for stage of cirrhosis. In a nested case-control study of cirrhotic adults awaiting LT (February 2002 to May 2011), cases were LT candidates with a liver-related death and MELD ≤ 20 within 90 days of death. Controls were similar LT candidates who were alive for ≥90 days after LT listing. NLR and other covariates were assessed at the date of lowest MELD, within 90 days of death for cases and within 90 days after listing for controls. There were 41 cases and 66 controls; MELD scores were similar. NLR 25th, 50th, 75th percentile cutoffs were 1.9, 3.1, and 6.8. NLR was ≥ 4 in 25/41 (61%) cases and in 17/66 (26%) controls. In univariate analysis, NLR (continuous ≥ 1.9, ≥ 4, ≥ 6.8), increasing cirrhosis stage, jaundice, encephalopathy, serum sodium, and albumin and nonselective beta-blocker use were significantly (P < 0.01) associated with liver-related death. In multivariate analysis, NLR of ≥1.9, ≥ 4, ≥ 6.8 were each associated with liver-related death. Furthermore, we found that NLR correlated with the frequency of circulating low-density granulocytes, previously identified as displaying proinflammatory properties, as well as monocytes. In conclusion, elevated NLR is associated with liver-related death, independent of MELD and cirrhosis stage. High NLR may aid in determining risk for cirrhotic decompensation, need for increased monitoring, and urgency for expedited LT in candidates with low MELD. Liver Transplantation 23 155-165 2017 AASLD., (© 2016 by the American Association for the Study of Liver Diseases.)

Purpose of Review: This article summarizes the landmark events that shaped current deceased donor liver allocation and distribution policy in the USA and to provide an update on recently approved and anticipated policy changes., Recent Findings: For liver transplant candidates with model for end-stage liver disease more than 11, the 'MELD-Na' equation incorporating serum sodium will be used for allocation starting January 2016. The 'delay and cap' policy for hepatocellular carcinoma delays the start of model for end-stage liver disease exception by 6 months and subsequently grants 28 points, with increases every 3 months thereafter up to a maximum score at 34 points. There is new guidance for exception petitions for neuroendocrine tumors, polycystic liver disease, and primary sclerosing cholangitis. New guidelines for selecting candidates for simultaneous liver-kidney transplant are being developed that may include a 'safety net' for liver-only recipients with posttransplant renal failure. In an effort to provide broader geographic sharing of livers than in the current distribution system, new larger geographic areas are being considered., Summary: Recent policy changes were designed to reduce waitlist mortality, yet inclusion of outcomes measures in allocation and the use of larger geographic distribution units will likely guide future policy changes.

Allocation policies for liver transplantation underwent significant changes in June 2013 with the introduction of Share 35. We aimed to examine the effect of Share 35 on regional variation in posttransplant outcomes. We examined two patient groups from the United Network for Organ Sharing dataset; a pre-Share 35 group composed of patients transplanted between June 17, 2012, and June 17, 2013 (n = 5523), and a post-Share group composed of patients transplanted between June 18, 2013, and June 18, 2014 (n = 5815). We used Kaplan-Meier and Cox multivariable analyses to compare survival. There were significant increases in allocation Model for End-stage Liver Disease (MELD) scores, laboratory MELD scores, and proportions of patients in the intensive care unit and on mechanical, ventilated, or organ-perfusion support at transplant post-Share 35. We also observed a significant increase in donor risk index in this group. We found no difference on a national level in survival between patients transplanted pre-Share 35 and post-Share 35 (p = 0.987). Regionally, however, posttransplantation survival was significantly worse in the post-Share 35 patients in regions 4 and 10 (p = 0.008 and p = 0.04), with no significant differences in the remaining regions. These results suggest that Share 35 has been associated with transplanting "sicker patients" with higher MELD scores, and although no difference in survival is observed on a national level, outcomes appear to be concerning in some regions., (© Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Liver transplantation can provide definitive cure for patients with cirrhosis and hepatocellular carcinoma (HCC) when used appropriately. Advances in the management of HCC have allowed improved control of HCC while waiting for liver transplantation and new approaches to candidate selection particularly with regard to tumor burden and downstaging protocols. Additionally, there have been recent changes in allocation policy related to HCC in the U.S. that cap the HCC MELD exception at 34 points and implement a 6-month delay in a HCC MELD exception. This review examines the U.S. liver transplant allocation policy related to HCC, comprehensively details locoregional therapy options in HCC patients awaiting liver transplantation, and considers the impact of an increasing burden of HCC on future liver graft allocation policy., (© 2015 American Association for the Study of Liver Diseases.)

We prospectively determined the prevalence of community-associated Staphylococcus aureus in a large cystic fibrosis (CF) center between October 2005 and October 2007. We found that 2.7% (19/707) of the CF patients who had cultures during the study period were infected with this organism, representing 14% of the total methicillin-resistant Staphylococcus aureus strains (n = 140) recovered from the patient population during the study period.

Background: The impact of infection with Burkholderia gladioli in cystic fibrosis, other chronic airway diseases and immunosuppressed patients is unknown., Methods: A six-year retrospective review of all patients with B. gladioli infection was performed in a tertiary referral center with cystic fibrosis and lung transplantation programs. In addition, a targeted survey of all 251 lung transplant recipients was performed. Available B. gladioli isolates were analyzed via pulsed field gel electrophoresis., Results: Thirty-five patients were culture positive for B. gladioli, including 33 CF patients. No bacteremia was identified. Isolates were available in 18 patients and all were genetically distinct. Two-thirds of these isolates were susceptible to usual anti-pseudomonal antibiotics. After acquisition, only 40% of CF patients were chronically infected (> or =2 positive cultures separated by at least 6 months). Chronic infection was associated with resistance to > or =2 antibiotic groups on initial culture and failure of eradication after antibiotic therapy. The impact of acquisition of B. gladioli infection in chronic infection was variable. Three CF patients with chronic infection underwent lung transplantation. One post-transplant patient developed a B. gladioli mediastinal abscess, which was treated successfully., Conclusions: The majority of patients' culture positive for B. gladioli at our center have CF. B. gladioli infection is often transient and is compatible with satisfactory post-lung transplantation outcomes.

The choice of antibiotics for sinusitis in children with cystic fibrosis (CF) is empirical or based on lower airway cultures, because sinus cultures are difficult to obtain. The aim of this study was to identify the main organisms cultured from CF children with chronic sinusitis, and to evaluate the concordance of concomitant sinus, oropharyngeal swab (OP), and bronchoalveolar lavage fluid (BALF) cultures. OP and BALF cultures were done preoperatively, and sinus cultures were obtained during clinically indicated sinus surgery. The genetic identity of the bacteria was compared if the same organisms were present in upper and lower airway cultures. In total, 45 paired sinus-BALF cultures from 31 patients were included. Twenty-four of these had matched OP cultures. The mean age of patients was 9.5 +/- 4.3 years, and 19 patients were DeltaF508 homozygous. Bacterial sinus infection was present in 96%, caused by S. aureus (49%), P. aeruginosa (42%), and H. influenzae (22%). The diagnostic accuracy of BALF or OP cultures was low in predicting sinus infection, particularly at younger ages. Positive and negative predictive values (PPV and NPV) of BALF for P. aeruginosa infection were 65% and 67%, and for S. aureus, 76% and 63%, respectively. Predictive values for OP cultures were similar. Bacterial species were the same in sinus and OP or BALF samples of 12 patients of these bacteria 83% showed genetic identity. We conclude that S. aureus is an important pathogen in pediatric CF sinusitis, and that BALF or oropharyngeal cultures are poor predictors for organisms present in the sinuses.