Judith Meza-Junco

Severe muscle depletion predicts postoperative length of stay but is not associated with survival after liver transplantation: Sarcopenia After Liver Transplantation

Muscle depletion or sarcopenia is associated with increased mortality in patients with cirrhosis; how it affects mortality after liver transplantation requires further study. In this study, we aimed to establish whether sarcopenia predicts increased morbidity or mortality after liver transplantation. We analyzed 248 patients with cirrhosis who had a computed tomography (CT) scan including the third lumbar vertebra before liver transplantation. Data were recovered from medical charts, the skeletal muscle cross‐sectional area was measured with CT, and sarcopenia was defined with previously published sex‐ and body mass index–specific cutoffs. One hundred sixty‐nine patients (68%) were male, and the mean age at transplantation was 55 ± 1 years. The etiologies of cirrhosis were hepatitis C virus (51%), alcohol (19%), autoimmune liver diseases (15%), hepatitis B virus (8%), and other etiologies (7%). Sarcopenia was present in 112 patients (45%), and it was more frequent in males (P = 0.002), patients with ascites (P = 0.02), and patients with higher bilirubin levels (P = 0.05), creatinine levels (P = 0.02), international normalized ratios (P = 0.04), Child‐Pugh scores (P = 0.002), and Model for End‐Stage Liver Disease scores (P = 0.002). The median survival period after liver transplantation was 117 ± 17 months for sarcopenic patients and 146 ± 20 months for nonsarcopenic patients (P = 0.4). Sarcopenic patients had longer hospital stays (40 ± 4 versus 25 ± 3 days; P = 0.005) and a higher frequency of bacterial infections within the first 90 days after liver transplantation (26% versus 15%, P = 0.04) in comparison with nonsarcopenic patients. In conclusion, sarcopenia is one of the most common complications in patients with cirrhosis and is predictive of longer hospital stays and a higher risk of perioperative bacterial infections after liver transplantation, but it is not associated with increased mortality. Liver Transpl 20:640–648, 2014.

Sarcopenic obesity and myosteatosis are associated with higher mortality in patients with cirrhosis

Obesity is frequently associated with cirrhosis, and cirrhotic patients may develop simultaneous loss of skeletal muscle and gain of adipose tissue, culminating in the condition of sarcopenic obesity. Additionally, muscle depletion is characterized by both a reduction in muscle size and increased proportion of muscular fat, termed myosteatosis. In this study, we aimed to establish the frequency and clinical significance of sarcopenia, sarcopenic obesity and myosteatosis in cirrhotic patients.

Inclusion of Sarcopenia Within MELD (MELD-Sarcopenia) and the Prediction of Mortality in Patients With Cirrhosis

OBJECTIVES:Limitations of the Model for End-Stage Liver Disease (MELD) score include its failure to assess the nutritional and functional status of cirrhotic patients. Our objectives were to evaluate the impact of sarcopenia in cirrhosis and whether the inclusion of muscularity assessment within MELD could improve the prediction of mortality in patients with cirrhosis.METHODS:We included 669 cirrhotic patients who were consecutively evaluated for liver transplantation. Skeletal muscle index at the third lumbar vertebra (L3 SMI) was measured by computed tomography, and sarcopenia was defined using previously published gender and body mass index–specific cutoffs. Using Cox proportional hazards regression, a novel MELD-sarcopenia score was derived.RESULTS:Sarcopenia was present in 298 patients (45%); sarcopenic patients had shorter median survival than non-sarcopenic patients (20±3 vs. 95±24 months, P<0.001). By Cox regression analysis adjusted for age, gender, and hepatocellular carcinoma, both MELD (hazard ratio (HR) 1.08, 95% confidence interval (CI) 1.06–1.10, P<0.001), and the L3 SMI (HR 0.97, 95% CI 0.96–0.99, P<0.001) were associated with mortality. Overall, the c-statistics for 3-month mortality were 0.82 (95% CI 0.78–0.87) for MELD and 0.85 (95% CI 0.81–0.88) for MELD-sarcopenia (P=0.1). Corresponding figures for 1-year mortality were 0.73 (95% CI 0.69–0.77) and 0.77 (95% CI 0.73–0.80), respectively (P=0.03). The c-statistics for 3-month mortality in patients with MELD<15 (0.85 vs. 0.69, P=0.02) and refractory ascites (0.74 vs. 0.71, P=0.01) were significantly higher for MELD-sarcopenia compared with MELD.CONCLUSIONS:Modification of MELD to include sarcopenia is associated with improved prediction of mortality in patients with cirrhosis, primarily in patients with low MELD scores. External validation of this prognostic index in larger cohorts of cirrhotic patients is warranted.

Severe muscle depletion predicts postoperative length of stay but is not associated with survival after liver transplantation.

We thank Drs. Clark and Cross for their interest in our study and will respond to their comments. We agree that one limitation of our study is that only patients who went on to receive liver transplantation were included, and patients who could have had sarcopenia might not have been listed. However, none of our patients evaluated for liver transplantation have been rejected solely on the basis of sarcopenia. The current evidence suggests that only “extreme sarcopenia,” previously defined differently as the lowest tertile of the total psoas area (TPA), the lowest quartile of the TPA, or the lowest sextile of the third lumbar skeletal muscle index, should be considered a contraindication for liver transplantation. On the other hand, in our cohort of patients, all underwent a nutritional evaluation as part of the liver transplant assessment with advice about increasing protein intake and leucine supplementation, but none of them had nasogastric or nasoenteral feeding. We normally used nasogastric or nasoenteral feeding only for those patients with a body mass index less than 18.5 kg/m because this has been shown to be a risk factor for mortality after liver transplantation, but none of the patients in this cohort had a body mass index below this threshold. Finally, because current methods used to assess liver disease severity, such as the Model for EndStage Liver Disease (MELD) score, do not give a functional assessment of the patient’s fitness, we believe that the next step is to evaluate the development of composite scores, including new scores such as MELD-sarcopenia and MELD-psoas, or to assign exemption points to those patients with sarcopenia so that they can undergo transplantation before they develop extreme sarcopenia. Nevertheless, this issue should be evaluated preferentially in prospective and multicenter controlled clinical trials.

Locoregional radiological treatment for hepatocellular carcinoma; Which, when and how?

Hepatocellular carcinoma (HCC) is one of the most frequent and deadliest cancers worldwide. Liver transplantation, surgical resection or local ablation offer the best survival advantages but most patients either present when the tumor is in an advanced stage or the degree of underlying liver disease precludes these options. Several therapies have been proposed for these patients with proven survival benefits. These therapies comprise the locoregional treatment for HCC, and include percutaneous ethanol injection (PEI), radiofrequency ablation (RFA), transarterial chemoembolization (TACE), transarterial radioembolization (TARE), and drug-eluting bead (DEB). PEI and RFA are considered curative treatments for early stage HCC; whereas TACE is a standard of care for intermediate stages. Additionally, evaluation of response to locoregional treatment in HCC is important, as objective response may become a surrogate marker for improved survival. Currently, there are several criteria for response assessment, including the World Health Organization (WHO), the Response Evaluation Criteria in Solid Tumors (RECIST), the European Association for the Study of the Liver Criteria (EASL), and the modified RECIST (mRECIST); however, there has been poor correlation between the clinical benefit provided by locoregional interventional therapies and conventional methods of response assessment. The aim of our study was to review and analyze the current evidence for radiological interventions in HCC, and to propose evidence based recommendations to improve the management of these patients.

Trastuzumab for gastric cancer

Background: Gastric cancer is a disease with different management approaches in different regions, especially between Western and Asian countries. Surgery is the mainstay of treatment for non-metastatic disease. Perioperative chemotherapy or adjuvant radio-chemotherapy is recommended, since recurrences are common after curative resection. Unfortunately, advanced or metastatic gastric cancer constitutes the majority of patients in clinical practice. For these patients systemic chemotherapy is the standard treatment, to provide palliation and prolong survival; however, prognosis remains poor. Several molecular targeting agents are under evaluation in international randomized studies. Objective: To review chemotherapy and targeted therapies for gastric cancer, chemical and pharmacological characteristics of trastuzumab, and evidence for its clinical use in gastric cancer. Methods: Examination of relevant literature. Results/conclusions: HER-2 is overexpressed/amplified in approximately 22% of gastric cancer patients. Trastuzumab, a recombinant humanized anti-HER-2 monoclonal antibody, is, to our knowledge, the first biological therapy that has showed a survival improvement by nearly 3 months (reduced risk of death by 26%), thus trastuzumab in combination with chemotherapy is a treatment option for patients with HER2-positive advanced gastric cancer. Trastuzumabs role in curative gastric cancer treatment needs to be studied, as well as monotherapy, maintenance therapy and second line treatment in the palliative setting.

Metastatic gastric cancer – focus on targeted therapies

Gastric cancer (GC) is currently the second leading cause of cancer death worldwide; unfortunately, most patients will present with locally advanced or metastatic disease. Despite recent progress in diagnosis, surgery, chemotherapy, and radiotherapy, prognosis remains poor. A better understanding of GC biology and signaling pathways is expected to improve GC therapy, and the integration of targeted therapies has recently become possible and appears to be promising. This article focuses on anti-Her-2 therapy, specifically trastuzumab, as well as other epidermal growth factor receptor antagonists such as cetuximab, panitumub, matuzumab, nimotzumab, gefitinib, and erlotinib. Additionally, drugs that target angiogenesis pathways are also under investigation, particulary bevacizumab, ramucirumab, sorafenib, sunitinib, and cediranib. Other targeted agents in preclinical or early clinical development include mTOR inhibitors, anti c-MET, polo-like kinase 1 inhibitors, anti-insulin-like growth factor, anti-heat shock proteins, and small molecules targeting Hedgehog signaling.

Cholangiocarcinoma: Has There been Any Progress?

Cholangiocarcinoma is the second most common primary hepatic tumour after hepatocellular carcinoma. Primary sclerosing cholangitis is one of the most commonly recognized risk factors for cholangiocarcinoma; however, approximately 90% of patients have no identifiable risk factors. Extrahepatic type is its most common presentation. Cholangiocarcinoma is considered to be a devastating disease, with a poor survival rate and few therapeutic options. Although surgical resection has been considered the best treatment option for localized cholangiocarcinoma, local recurrences of this cancer are very common, and imply persistent micro-metastatic disease in lymph nodes or at surgical margins, even after extended surgical resection. Consequently, the five year survival rate after attempted curative resection is only 20% to 40%. Early studies of liver transplantation for cholangiocarcinoma did not show a survival benefit and, currently, this tumour is considered to be an absolute contraindication for liver transplantation in most transplant centres worldwide. Recently, neoadjuvant chemoradiation in combination with liver transplantation for highly selected patients with cholangiocarcinoma has shown impressive results, with five-year survival rates at approximately 76% to 82%--similar to other standard indications for liver transplantation, such as hepatocellular carcinoma or hepatitis C-induced cirrhosis. However, this success of liver transplantation applies to only a subset of patients and most of the data originated from a single centre. Wider application of this strategy, especially for patients with potentially resectable disease, will require validation by other centres.

Critical appraisal of trastuzumab in treatment of advanced stomach cancer.

Advanced or metastatic gastric cancer constitutes the majority of patients in clinical practice. In North America, about 70% of cases are advanced or metastatic when diagnosed, which is higher than the 50% reported in Japan. This difference in presentation is reflected in 5-year overall survival, which is about 20% in North America and 40%–60% in Japan. Despite numerous efforts of randomized studies on advanced gastric cancer, no globally accepted standard regimen has yet been established. Systemic chemotherapy provides palliation and prolongs survival, but the prognosis remains poor. Several monotherapies and combined regimens are currently available and vary around the world. Additionally, several molecular targeting agents are under evaluation in international randomized studies. Human epidermal growth factor receptor-2 (HER-2) is overexpressed or amplified in approximately 22% of patients with gastric cancer. Trastuzumab, a recombinant humanized anti-HER-2 monoclonal antibody, is the first biological therapy that has showed a survival improvement by nearly three months (reduced risk of death by 26%). Therefore, trastuzumab in combination with cisplatin is a reasonable treatment option for patients with advanced gastric cancer who are HER-2 positive. This paper will focus on trastuzumab, its chemical and pharmacological characteristics, and the relevant efficacy, safety, and tolerability studies.

Transarterial chemoembolization in patients with hepatocellular carcinoma: predictors of survival.

BACKGROUND Transarterial chemoembolization (TACE) is the mainstay of management for patients with hepatocellular carcinoma who are not suitable for curative treatments. OBJECTIVE To determine factors associated with mortality after the first TACE procedure. METHODS From January 2004 to May 2008, 60 patients underwent TACE as treatment for hepatocellular carcinoma. Clinical and biochemical parameters before TACE, and response after TACE, were evaluated with conventional classifications (WHO, Response Evaluation Criteria in Solid Tumors [RECIST], and European Association for the Study of the Liver [EASL] criteria) and with one-, two- and three-dimensional assessment. RESULTS Overall median survival after the first TACE procedure was 17.1±3.4 months. According to Cox regression analysis, having an alpha-fetoprotein level of greater than 200 ng⁄mL (HR 2.35 [P=0.02]) and a Model for End-stage Liver Disease (MELD) score of greater than 10 (HR 4.19 [P=0.001]) were associated with higher risk of mortality; whereas reduction in tumour size measured in one dimension (HR 0.96 [P=0.005]), two dimensions (HR 0.98 [P=0.004]) and three dimensions (HR 0.98 [P=0.001]) was associated with lower risk of mortality. Moreover, reduction in tumour size by 3% or more assessed in one, two or three dimensions was associated with lower risk of mortality (HR 0.48 [P=0.04]; HR 0.36 [P=0.01]; HR 0.31 [P=0.003], respectively). The three conventional classifications were not useful for predicting mortality (WHO: HR 1.07 [P=0.9]; RECIST: HR 0.94 [P=0.9]; EASL: HR 0.94 [P=0.9]). CONCLUSIONS Having an alpha-fetoprotein level of greater than 200 ng⁄mL and a MELD score of greater than 10 before undergoing TACE was associated with a greater risk of mortality. Conventional classifications of response were not useful for predicting mortality. Reduction in tumour size after the first TACE procedure was associated with better survival, primarily if patients had more than a 3% reduction in tumour size assessed by three-dimensional measurement.