Therapies for Patients with Hepatocellular Carcinoma Awaiting for Liver Transplantation: a Systematic Review and Meta-analysis

Abstract

Patients with hepatocellular carcinoma (HCC) who are listed for liver transplantation are often treated while on the waiting list with loco-regional therapy (LRT) which is aimed at either preventing progression of HCC or reducing themeasurable disease burden of HCC in order to receive increased allocation priority. We aimed to synthesize evidence regarding the effectiveness of LRT in the management of patients with HCC who were on the liver transplant waitlist. We conducted a comprehensive search of multiple databases from 1996 to April 25, 2016, for studies that enrolled adults with cirrhosis awaiting liver transplantation and treated with bridging or down-staging therapies before liver transplantation. Therapies included trans-catheter arterial chemoembolization (TACE), trans-arterial radio-embolization (TARE), ablation or radiotherapy. We included both comparative and non-comparative studies. There were no randomized controlled trials identified. Results: For adults with T1 HCC and waitingfor liver transplantation there were only 2 non-randomized comparative studies, both with a high risk of bias, which reported the outcome of interest. In one series, the rate of dropout from all causes at 6 month in T1 HCC patients underwent loco-regional therapy was 5.3%, while in the other series of T1 HCC patients who did not receive loco-regional therapy, dropout rate at median follow up of 2.4 years and progression rate to T2 HCC was 30% and 88% respectively. For adults with T2 HCC awaiting liver transplantation, transplant with any bridging therapy showed a non-significant reduction in the risk of waitlist dropout due to progression (RR 0.32 (95% CI 0.06 - 1.85, I2 = 0%) and waitlist dropout from all causes (RR 0.38 (95% CI 0.060 - 2.370, I2=85.7%), compared to no therapy based on 3 comparative studies. The quality of evidence is very low due to high risk of bias, imprecision and inconsistency. There were 5 comparative studies which reported on post-transplant survival rates and 10 comparative studies which reported on post-transplant recurrence and there was no significant difference seen in either of these endpoints. For adults initially with stage T3 HCC who got LRT, there were 3 studies available reporting on transplant with any down-staging therapy versus no down-staging and this showed significant increase in 1year (2 studies (51, 52)(RR 1.11 (95% CI 1.01-1.23) and 5 year (1 study (52) (RR 1.17 (95% CI 1.03-1.32)post-LT survival rates for the patients who received LRT. The quality of evidence is very low due to serious risk of bias and imprecision.Conclusion: in patients with HCC listed for liver transplantation, the use of LRT is associated with a non-significant trend toward improved waitlist and post-transplant outcomes, though there is a high risk of selection bias in the available evidence. This article is protected by copyright. All rights reserved.

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Projections of primary liver cancer to 2030 in 30 countries worldwide

ABSTRACT

Primary liver cancer (PLC) is the sixth most common cancer worldwide and the second most common cause of cancer death. Future predictions can inform health planners and raise awareness of the need for cancer control action. We predicted the future burden of PLC in 30 countries around 2030. Incident cases of PLC (ICD-10 C22) were obtained from 30 countries for 1993-2007. We projected new PLC cases through to 2030 using age-period-cohort models (NORDPRED). Age-standardized incidence rates per 100,000 person-years were calculated by country and sex. Increases in new cases and rates of PLC are projected in both sexes. Among men, the largest increases in rates are in Norway (2.9% per annum), US whites (2.6%), and Canada (2.4%), and among women in the US (blacks 4.0%), Switzerland (3.4%), and Germany (3.0%). The projected declines are in China, Japan, Singapore, and parts of Europe (e.g. in Estonia, Czech Republic, Slovakia). A 35% increase in the number of new cases annually is expected compared to 2005. This increasing burden reflects both increasing rates (and the underlying prevalence of risk factors) and demographic changes. Japan is the only country with a predicted decline in the net number of cases and annual rates by 2030. Conclusion: Our reporting of a projected increase in PLC incidence to 2030 in 30 countries serves as a baseline for anticipated declines in the longer-term via the control of HBV and HCV infections through vaccination and treatment. However, the prospects that rising levels of obesity and its metabolic complications may lead to an increased increasing risk of PLC that potentially offset these gains, is a concern. This article is protected by copyright. All rights reserved.

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Imaging for the Diagnosis of Hepatocellular Carcinoma: a Systematic Review and Meta-analysis

Abstract

Multiphasic computed tomography (CT) and magnetic resonance imaging (MRI) are both used for non-invasive diagnosis of hepatocellular carcinoma (HCC) in patients with cirrhosis. To determine if there is a relative diagnostic benefit of one over the other, we synthesized evidence regarding the relative performances of CT, extracellular-contrast-enhanced-MRI, and gadoxetate-enhanced-MRI for diagnosis of HCC in patients with cirrhosis. We also assessed whether liver biopsy versus follow-up with the same versus alternative imaging is best for CT- or MRI-indeterminate liver nodules in patients with cirrhosis. We searched multiple databases from inception to April 27, 2016 for studies comparing CT with extracellular-contrast-enhanced-MRI or gadoxetate-enhanced-MRI in adults with cirrhosis and suspected HCC. Two reviewers independently selected studies and extracted data. Of 33 included studies, 19 were comprehensive, while 14 reported sensitivity only. For all tumor sizes, the 19 comprehensive comparisons showed significantly higher sensitivity (0.82 vs. 0.66) and lower negative likelihood ratio (0.20 vs. 0.37) for MRI over CT. The specificities of MRI vs. CT (0.91 vs. 0.92) and the positive likelihood ratios (8.8 vs. 8.1) were not different. All three modalities performed better for HCCs ≥2 cm. Performance was poor for HCCs <1 cm. No studies examined whether adults with cirrhosis and an indeterminate nodule are best evaluated using biopsy, repeated imaging or alternative imaging. Concerns about publication bias, inconsistent study results, low study quality, and clinical factors precluded support for exclusive use of either gadoxetate-enhanced or extracellular-contrast-enhanced MRI over CT. Conclusion: CT, extracellular-contrast-enhanced-MRI or gadoxetate-enhanced-MRI could not be definitively preferred for HCC diagnosis in patients with cirrhosis. In patients with cirrhosis and an indeterminate mass, there was insufficient data comparing biopsy to repeat cross-sectional imaging or,alternative imaging. This article is protected by copyright. All rights reserved.

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Cystathionine β-synthase is required for body iron homeostasis

Abstract

Cystathionine β-synthase (CBS) catalyzes the transsulfuration pathway and contributes, among other functions, to the generation of hydrogen sulfide (H₂S). In view of the exceptionally high expression of CBS in the liver and the common interleukin-6 (IL-6) pathway utilized in the regulatory systems of H₂S and hepcidin, we speculate that CBS is involved in body iron homeostasis. We found that CBS knock-out (CBS^-/-) mice exhibited anemia and a significant increase in iron content in the serum, liver, spleen and heart, along with severe damage to the liver, displaying a hemochromatosis-like phenotype. A high level of hepatic and serum hepcidin was also found. A major cause of the systemic iron-overload is the reduced iron utilization due to suppressed erythropoiesis, which is consistent with an increase in IL-6 and the reduced expression of erythropoietin. Importantly, in the liver, an absence of CBS caused both a reduction in the transcriptional factor NRF2 and an upregulation of hepcidin that lead to a decrease in the iron export protein ferroportin 1. The resulting suppression of iron export exacerbates iron retention, causing damage to hepatocytes. Finally, administration of CBS-overexpressing adenovirus into CBS mutant mice could partially reverse the iron-related phenotype. Our findings thus point to a previously unknown, yet critical role of CBS in iron homeostasis of the body, and the liver in particular. It is likely that a hemochromatosis-like phenotype in patients can be induced by aberration not only in the expression of key molecules in the hepcidin pathway, but also in those related to CBS. This article is protected by copyright. All rights reserved.

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Pregnancy in Wilson disease – management and outcome

Abstract

Introduction

Wilson disease (WD) is a rare inherited disorder of copper metabolism causing toxic hepatic and neural copper accumulation. Clinical symptoms vary widely, from asymptomatic disease to acute liver failure or chronic liver disease without or with neuropsychiatric symptoms. Continuation of specific medical treatment for WD is recommended during pregnancy, but reports of pregnancy outcomes in WD patients are sparse.

Patients and methods

In a retrospective, multicenter study, 282 pregnancies in 136 WD patients were reviewed. Age at disease onset, age at conception and WD-specific treatments were recorded. Maternal complications during pregnancy, rate of spontaneous abortions and birth defects were analyzed with respect to medical treatment during pregnancy.

Results

Worsening of liver function tests was evident during 16/282 (6%) pregnancies and occurred in undiagnosed patients as well as in those under medical treatment. Liver test abnormalities resolved in all cases after delivery. Aggravation of neurological symptoms during pregnancy was rare (1%) but tended to persist after delivery. The overall spontaneous abortion rate in the study cohort was 73/282 (26%). Patients with an established diagnosis of WD receiving medical treatment experienced significantly fewer spontaneous abortions than patients with undiagnosed WD (Odds ratio: 2.853 [95% CI: 1.634-4.982]). Birth defects occurred in 7/209 (3%) live births.

Conclusion

Pregnancy in WD patients on anti-copper therapy is safe. The spontaneous abortion rate in treated patients was lower than that in therapy-naive patients. Although the teratogenic potential of copper chelators is a concern, the rate of birth defects in our cohort was low. Treatment for WD should be maintained during pregnancy, and patients should be monitored closely for hepatic and neurologic symptoms. This article is protected by copyright. All rights reserved.

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Keytruda (pembrolizumab) in Patients with Multiple Myeloma: FDA Statement - Two Clinical Trials on Hold

Audience: Oncology [Posted 08/31/2017] ISSUE: Based on data from two recently halted clinical trials, the U.S. Food and Drug Administration today is issuing this statement to inform the public, health care professionals, and oncology clinical...

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Keytruda (pembrolizumab) in Patients with Multiple Myeloma: FDA Statement - Two Clinical Trials on Hold

Audience: Oncology [Posted 08/31/2017] ISSUE: Based on data from two recently halted clinical trials, the U.S. Food and Drug Administration today is issuing this statement to inform the public, health care professionals, and oncology clinical...

http://ift.tt/2em8Be3