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Current Issue

January March, 2011

Vol. 10 Issue 1

On the cover: Contrast enhanced CT scan, revealing a well defined hypodense mass.

HEPATOLOGY HIGHLIGHTS

CONCISE REVIEW

  • Treatment issues surrounding hepatitis C in renal transplantation: A review Edward Kim, Hin Hin Ko, Eric M. Yoshida Page 5-14

    Hepatitis C infection is prevalent in candidates for and recipients of solid organ transplants. In the renal transplant population, HCV infection has been shown to decrease long-term patient and graft survival. The outcomes of HCV in recipients of other solid organ transplants are yet to be established and prospective studies will be needed in the future. In the absence of effective and safe antiviral treatment for HCV infection in renal, heart, and lung transplant recipients, the management of these patients remains a challenge and has led to an increased focus on identifying and treating hepatitis C in patients prior to transplantation. Interferon-based therapy for HCV prior transplantation appears to improve outcomes after transplantation. On the other hand, post-transplant interferon therapy is associated with an increased risk of graft rejection. Given the paucity of information on HCV treatment in solid organ transplant recipients, there is a great need for large-scale, multi-centre randomized controlled trials to determine the optimal approach to HCV infection in this population. This article will summarize the current peer-reviewed literature focusing on the efficacy of amantadine, ribavirin and both standard and pegylated interferon in the treatment of chronic hepatitis C in renal, transplant recipients.

ORIGINAL ARTICLES

Clinical Studies

  • Prevalence and risk factors for bacterial skin infection and mortality in cirrhosis Pazhanivel Mohan, Bhavadharani Ramu, Emmanuel Bhaskar, Jayanthi Venkataraman Page 15-20

    Background. Bacterial infections are often associated with significant morbidity and mortality in cirrhosis. The common practice of outdoor barefoot walking in the developing world may predispose cirrhotic individuals to skin infection. Aims. To determine the prevalence, risk factors, spectrum of infective organism and outcome of bacterial skin infection in cirrhosis. Methods. Consecutive newly diagnosed patients with cirrhosis (n = 200) between September 2007 and September 2008 were studied. Patients with congestive heart failure (n = 50) and chronic kidney disease (n = 50) on follow up at the same institution served as controls. Baseline demographic details, history of outdoor barefoot walking, details of skin infection along with cultures from skin and blood were obtained. The association between patient factors and risk of skin infection was evaluated using logistic regression. Results. Alcoholism was the predominant etiology for cirrhosis. (50%) Most of them were of Child B cirrhosis. Walking on barefoot was found to be similar in cases and controls. 21(10.5%) patients with cirrhosis had skin infection, three fourth of them had a history of barefoot walking. None of the controls had skin infection. Cellulitis with hemorrhagic bullae, leg ulcers, infected callosity and abscess were observed. The infective organism could be isolated in 17 patients. Escherichia coli was the most frequent organism identified. Logistic regression showed outdoor barefoot walking and serum albumin < 2.5 gm/dL as risk factors for skin infection. Four patients died. Conclusion. The prevalence of skin infection in cirrhosis was 10.5% with a mortality of 19%. Escherichia coli was the commonly implicated organism. Outdoor barefoot walking was a strong risk factor for skin infection in cirrhosis.

  • Advanced hepatocellular carcinoma.Review of targeted molecular drugs Rogério Camargo Pinheiro Alves, Daniele Alves, Betty Guz, Carla Matos, Monica Viana, Michele Harriz, Deborah Terrabuio, Mario Kondo, Otavio Gampel, Paula Polletti Page 21-27

    Hepatocellular carcinoma (HCC) is the sixth most common cancer in the world in terms of incidence, accounting for approximately 630 thousand new cases per year; in addition, HCC is the third most common cause of cancer death. Worldwide, the greatest risk factors for HCC are the infections caused by hepatitis B and C viruses, which increase the risk of developing the disease by about 20 times. The standard treatment in the early stages of the disease, such as surgical resection, local ablation and liver transplantation, are able to cure a proportion of patients, but most cases of HCC present in advanced stages, precluding the use of such treatments with curative intent. In these advanced stages, systemic treatments are commonly used. Unfortunately, chemotherapy with conventional cytotoxic agents is ineffective and does not seem to modify the natural history of disease. Treatment options for patients with advanced HCC are extremely limited, but the identification of signaling pathways, and the recognition of the role of these pathways in the pathogenesis of the disease resulted in the development of drugs directed at specific therapeutic targets. One such drug is Sorafenib, a kinase inhibitor with antiangiogenic and antiproliferative properties. In conclusion, Sorafenib has demonstrated survival benefits in patients with advanced HCC, thus representing a new standard reference for systemic treatment in these cases.

  • Does HLA-DR7 differentiate the overlap syndrome of auto-immune hepatitis-primary biliary cirrhosis (AIH-PBC) from those with auto-immune hepatitis type 1? Aldo Torre Page 28-32

    Introduction. Autoimmune hepatitis (AIH) and overlap-syndrome (OS) are autoimmune liver diseases of unknown etiology. Although HLA-DR3/DR4 plays a susceptibility role in AIH but there is limited information in regard to OS. Objective. Determine the genetic expression of HLA-DR among patients with AIH versus OS in order to establish susceptibility alleles in comparison to healthy controls (HC). Methods. 26 patients with AIH and 15 patients with OS were studied. Ninety-nine healthy historical controls without autoimmunity were evaluated. Patients with AIH and OS were selected based on the international group for the study of AIH criteria and the Chazouilleres criteria for OS. Patients had at least one liver biopsy. Characterization of HLA-DR was extracted from peripheral blood leukocytes. Alleles were obtained for AIH, OS and HC and comparisons were made between groups. Results. There was a significant increase in HLADR3 and DR1 in AIH compared with the HC group (p = 0.04, OR 2.6, 0.87-7.9, 95% CI). In the AIH group there was a decreased frequency in allele HLA-DR8 when compared with HC (p = 0.04, OR 3.2). There were no statistical differences between the genetic frequencies in the OS group compared with HC. However, HLA-DR7 was able to distinguish between OS patients from those with AIH (p = 0.02, OR 9.8, 1.02-233.6, 95% CI). Conclusions. HLA-DR1/DR3 is increased in AIH, but contrary to data reported in AIH, HLA-DR7 frequency is increased in OS, suggesting increased susceptibility which distinguishes patients with AIH from those with OS.

  • Nonalcoholic fatty liver disease in Brazil. Clinical and histological profile Helma P. Cotrim, Edison R. Parise, Claudia P.M.S. Oliveira, Natalhie Leite, Ana Martinelli, Joao Galizzi, Rita de Cássia Silva, Ângelo Mattos, Leila Pereira, Waldir Amorim, Claúdia Ivantes, Francisco Souza, Marcelo Costa, _ Maia Page 33-37

    Background. The epidemiology and clinical characteristics of nonalcoholic fatty liver disease (NAFLD) in South America are not well known. Brazil is a largest country in this part of the world and the present study aimed to contribute with this information. Methods. This descriptive study included patients from medical centers around Brazil, who had diagnosis of NAFLD. They were selected from chart review and also prospectively in Hepatology out-clinics. Patients with history of alcohol intake and others liver diseases were excluded. Histological diagnosis included: steatosis or steatohepatitis (steatosis, ballooning of hepatocytes or fibrosis). The criteria to perform a liver biopsy was ALT or AST > 1.5 x normal levels. Results. A total of 1280 patients from 16 Brazilian centers and all five regions were included. The mean age was 49.68 ± 13.59 years; 53.3% were males and 85% were asymptomatic. Hyperlipidemia was observed in 66.8% cases, obesity in 44.7%, overweight in 44.4%, diabetes in 22.7%, and toxins exposure in 10%. Metabolic syndrome was observed in 41.3% cases. Elevated levels of ALT, AST and GGT were observed in 55.8%, 42.2% and 63.1% cases, respectively. Liver biopsy performed in 437 cases showed: isolate steatosis in 42% cases, steatohepatitis in 58% and 27% of them also presented fibrosis. Cirrhosis was observed in 15.4% and hepatocellular carcinoma in 0.7%. Conclusions. NAFLD in Brazil is more frequent in asymptomatic males; steatohepatitis with fibrosis and cirrhosis were a significant diagnosis. The genetic predisposition and lifestyle should be influenced in the spectrum; however these findings deserve a future investigation.

  • Liver transplantation: A new risk factor for intestinal intussusceptions Sven Pischke, Wursthorn Karsten, Johannes Hadem, Sebastian Schmidt, Karl Heiringhoff Heinz, Fabian Helfritz, Christian P. Strassburg, Joachim Lobers, Lars Zender, Oktay Tutarel, Jochen Wedemeyer, Michael P. Manns, Heiner Wedemeyer, _ Rifai Page 38-42

    Background. Intestinal intussusception in adults is associated with chronic inflammatory bowel disease, coeliac disease, abdominal tumors or previous abdominal surgery but most often of unknown origin. Aim. The aim of our study was to evaluate circumstances and identify risk factors for intussusceptions. Methods. All 65,928 abdominal ultrasound examinations performed at our tertiary medical center between January 2001 and June 2008 were analyzed retrospectively for the diagnosis "intussusception". After identifying individuals with sonographically proven intussusception we analyzed various patients' characteristics including age, gender and underlying disease as well as sonographic findings such as localization of the intussusception, absence or presence of ascites and lymph nodes. Results. We identified 32 cases of intussusceptions [mean age 45 years (range 18 to 88); 18 patients were male]. Twelve patients (38%) had a history of abdominal surgery including 8 patients who had undergone liver transplantation (2 patients with primary sclerosing cholangitis, 1 patient with cystic fibrosis, 1 patient with sarcoidosis, 1 patient with hepatocellular carcinoma and HCV infection, 1 patient with autoimmune hepatitis, 1 patient with Crigler-Najar-syndrome and one patient with echinococcus). A hepaticojejunostomy had been performed in 4 of the patients after liver transplantation. Liver transplanted patients were significantly overrepresented in the intussusception group compared with the overall cohort of patients undergoing abdominal ultrasound examination (25% vs. 8%, Chi-Square-test, p = 0.0023).

  • Epidemiological assessment of liver disease in northeastern Brazil by means of a standardized liver biopsy protocol Lucas Lembrança, Jéssica Medina, Marcelo Portugal, Delvone Almeida, Jorge Solla, Ricardo Gadelha, Luiz A.R. de Freitas, Raymundo Paraná Page 43-49

    Background/Aims. The main objective of this study was to describe the profile of patients who were benefitted in a collective effort to perform liver biopsies in Bahia, Brazil. Methods. A cross-sectional study was conducted with a sample composed of all the patients who were submitted to liver biopsy during a collective effort carried out in Bahia between July 2007 and November 2009. At the time of the procedure, data on the age and gender of patients and the reason for performing the biopsy were recorded. Data on the degree of fibrosis and the presence of co-morbidities. Following statistical analysis, the frequency of the liver diseases that led to the biopsy procedure was described, and the profile of the patients was stratified into groups according to the most prevalent etiologies. Results. Of the 550 patients evaluated, 55.3% were men and 44.7% women. Mean age was 46.63 ± 11.59 years and there was no statistically significant difference in age between males and females. Of the 550 patients, 72% had hepatitis C and the mean age of these patients was 48.49 ± 10.1 years, significantly higher than the mean age of the patients with hepatitis B (40.41 ± 12.43 years). Furthermore, 70.7% of the patients with hepatitis C were between 41 and 60 years of age. The most frequent fibrosis grade was F2 (44%) and the prevalence of advanced fibrosis was 27.7%. Overall, 85 patients, most of them men, had some degree of iron overload. With respect to the safety of the biopsy procedure, severe complications occurred in only two patients. Conclusion. Hepatitis C is the predominant liver disease that demanded liver biopsy. The profile of the patients who benefitted from this collective effort is similar to that of patients in the rest of the country. Moreover, non-Ultrasonography guided liver biopsy is safe and the collective effort to carry out liver biopsies in Bahia was found to be a viable venture.

  • Relation of osteocalcin with insulin resistance and histopathological changes of non alcoholic fatty liver disease Rocio Aller, Jose Luis Perez Castrillon, Daniel Antonio de Luis, Rocio Conde, Olatz Izaola, Manuel González Sagrado, María Concepción Velasco, Tomas Alvarez, David Pacheco Page 50-55

    Background. Osteocalcin is a hormone with a complex cross-talk between adipose tissue and the skeleton. The aim of the present study was to explore the relation of osteocalcin with histopathological changes of NALFD patients. Subjects. A population of 69 NAFLD patients was analyzed. A liver biopsy was realized. Weight, fat mass, body mass index, basal glucose, insulin, insulin resistance (HOMA), total cholesterol, LDLcholesterol, HDL-cholesterol, triglycerides and osteocalcin levels were measured. Results. Patients were divided in two groups by median osteocalcin value (11.34 ng/mL), group I (patients with the low values) and group II (patients with the high values). Only liver fibrosis frequencies were different between groups (group I: 22.9% vs group II: 9.4%; p < 0.05). Patients in group I had higher levels of glucose (115.6 ± 28.1 mg/ dL vs. 103.7 ± 24.3 mg/dL; p < 0.04), HOMA (4.6 ± 3.1 units vs. 3.6 ± 1.8 units; p < 0.04), weight (102.9 ± 32.4 kg vs. 85.9 ± 16.8 kg; p = 0.002) and body mass index (38.3 ± 11.4 kg/m2 vs. 30.1 ± 5.7 kg/m2; p = 0.001)) than patients in group II. Osteocalcin was inverse correlated with glucose (r =-0.4; p = 0.002) and HOMA (r = -0.3:p = 0.01). Conclusion. Osteocalcin is associated with liver fibrosis. However, this association disappeared in a multivariate analysis, and HOMA remained as an independent factor.

  • The impact of diabetes mellitus in mortality of patients with compensated liver cirrhosis-a prospective study Joel Omar Jáquez-Quintana, Diego García Compean, José Alberto González-González, Jesús Zacarías Villarreal-Pérez, Fernando Javier Lavalle-González, Linda Elsa Muñoz Espinosa, Pedro López Hernández, Erick Reyes-Cabello, Edgar Redondo Villarreal, Ricardo Flores-Rendón, Héctor Maldonado-Garza Page 56-62

    Background. It has been suggested that DM may reduce survival of patients with liver cirrhosis (LC). Nevertheless only few prospective studies assessing the impact of DM on mortality of cirrhotic patients have been published, none in compensated LC. Aims. (i) to study the impact of DM on mortality and (ii) to identify predictors of death. Methods. Patients with compensated LC with and without DM were studied. Survival was analyzed by the Kaplan-Meier Method. Univariate and multivariate analysis was performed to determine independent predictors of mortality. Results. 110 patients were included: 60 without DM and 50 with DM. Diabetic patients had significantly higher frequency of cryptogenic cirrhosis, anemia, hypoalbuminemia, and hypercreatininemia. They also had significantly higher BMI and Child-Pugh score. The 2.5- years cumulative survival was significantly lower in patients with DM (48 vs. 69%, p < 0.05). By univariate analysis: DM, female gender, serum creatinine > 1.5 mg/dL, Child-Pugh score class C and cryptogenic cirrhosis were significant. However, only serum creatinine > 1.5 mg/dL and Child-Pugh score class C were independent predictors of death. Conclusion: DM was associated with a significant increase in mortality in patients with compensated liver cirrhosis. Serum creatinine > 1.5 mg/dL and Child-Pugh score class C were independent predictors of death.

ORIGINAL ARTICLES

Basic studies

  • Protective and curative effects of polyphenolic extracts from Ichnocarpus frutescense leaves on experimental hepatotoxicity by carbon tretrachloride and tamoxifen Chidambaram Kumarappan, Madhavan Vijayakumar, Ellappan Thilagam, Manikam Balamurugan, Madheswaran Thiagarajan, Siddan Senthil, Sunil C. Das, Subhash C. Mandal Page 63-72

    carpus frutescense against carbon tetrachloride and tamoxifen induced hepatotoxicity in rats. Carbon tetrachloride and tamoxifen caused liver damage in rats manifested by significant rise in serum enzymes levels. Models of carbon tetrachloride and tamoxifen intoxication elicited significant declines in the reduced glutathione concomitant with significant elevations in malondialdehyde levels. The oral administration of polyphenolic extract to carbon tetrachloride and tamoxifen intoxicated ats, produced significant increments in the reduced glutathione concomitant with significant decrements in malondialdehyde and liver transaminases levels. Prophylactic and curative treatments with the polyphenolic extract generally resulted in a relatively good protection against both carbon tetrachloride and tamoxifen intoxicated rats. The histopathological changes of liver sections showed an improved histological appearance. The extract inhibits CYP monoxygenases aminopyrine-N-demethylase and aniline hydroxylase, suggesting a plausible hepatoprotective mechanism. However prophylactic treatment with the polyphenolic extract exhibited a higher activity compared to curative treatment. The normalization of phenobarbitone induced sleeping time suggests the restoration of liver CYP enzymes. The study shows that hepatoprotective activity of polyphenol extract is by regulating the levels of hepatic microsomal drug metabolising enzymes. These results supported the use of this plant for the treatment of hepatitis in oriental traditional medicine.

  • Protective effect of four Mexican plants against CCl4-induced damage on the Huh7 human hepatoma cell line Liliana Torres-González, Linda Elsa Muñoz Espinosa, Ana María Rivas-Estilla, Karina Trujillo-Murillo, Ricardo Salazar-Aranda, Noemi Waksman De Torres, Paula Cordero-Pérez Page 73-79

    Background. Centaurea americana, Krameria ramosissima, Juglans mollis and Turnera diffusa are used by traditional healers in the northeastern region of Mexico to protect against liver damage. However, the hepatoprotective properties of these plants have not been investigated scientifically. This study reports on the protective effects of these plants using an in vitro assay. Material and methods. Extracts of plants were tested for antioxidant activity using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging method. The effects of extracts from these plants on a human hepatoma cell line (Huh7) were evaluated according to cell viability and aspartate aminotransferase and malondialdehyde levels before and after exposure of the cells to carbon tetrachloride (CCl4). Results. All extracts reduced DPPH levels by more than 50%. C. americana flower and stem/leaf extracts, the aerial part of T. diffusa, and the nut, leaf and bark of J. mollis extracts were used to assess hepatoprotective activity. The extract of the aerial part of K. ramosissima was toxic. Pretreatment of Huh7 cells with extracts from the flower of C. americana (FCA), the stem/leaf fraction of C. americana (S/LCA), the leaf of J. mollis (LJM) and the bark of J. mollis (BJM) prior to the CCl4 challenge, protected against CCl4-induced liver damage, as evidenced by a significant decrease in the activity of the medium enzyme. The FCA, S/LCA, LJM and BJM extracts showed significant antilipid peroxidant effects in vitro. In conclusion, the hepatoprotective effects of the FCA, S/LCA, LJM and BJM extracts observed in this study may result from their antioxidative properties.

IMAGES IN HEPATOLOGY

CASE REPORTS

  • Undifferentiated embryonal sarcoma of liver in an adult masquerading as complicated hydatid cyst Naveen Kalra, Sammer Vyas, Palash Jyoti Das, Rakesh Kochhar, Radhika Srinivasan, Niranjan Khandelwal Page 81-83

    Benign or malignant hepatic lesions may rarely mimic inflammatory lesions on imaging. We describe a case of young adult male presenting with pain abdomen and fever of short duration. Imaging revealed large complex multiseptated lesion in the right lobe of liver. Complicated hydatid cyst was kept as first differential diagnosis depending on clinic-radiologic findings. However, due to few atypical imaging features, FNAC of the lesion was performed which confirmed the lesion as UESL.

  • Effectiveness of add-on Pegylated interferon alfa-2a therapy in a Lamivudine-treated patient with chronic hepatitis B Carmelo Mangano, Giovanni Squadrito, Irene Cacciola, Mariastella Carpentieri, Giuseppe Foti, Giovanni Raimondo Page 84-87

    Hepatitis B virus (HBV) surface antigen (HBsAg) to anti-HBsAg (anti-HBs) antibody seroconversion is the best, final objective for all available chronic hepatitis B (CHB) treatments. Unfortunately, this goal is rarely obtained with the currently utilized therapeutic approaches. Here we describe the case of a CHB patient who was very successfully treated with a particular therapeutic schedule. The patient was initially treated with Lamivudine for four years. Subsequently, pegylated interferon alpha-2a was introduced for a period of one year. During this period of combined therapies, the patient showed a flare of aminotransferase values followed by complete normalization of liver biochemistry parameters and HBsAg/anti-HBs seroconversion that persisted up to 24 months after all therapies had been stopped.

  • Arcuate ligament compression as a cause of early-onset thrombosis of the hepatic artery after liver transplantation Mario Vilatobá, Daniel Zamora-Valdés, Manuel Guerrero-Hernández, Héctor Romero-Talamás, Rafael P. Leal-Villalpando, Miguel A. Mercado Page 88-92

    Background. Early hepatic artery thrombosis (HAT) is a potentially lethal complication after orthotopic liver transplantation (OLT) requiring immediate intervention. Aim. To report an infrequent cause of HAT after OLT and by itself a controversial clinical entity, the median arcuate ligament celiac artery compression. Case report. A 59-year-old female with hepatitis C virus-induced cirrhosis, Child B, MELD 15, underwent cadaveric-donor OLT with complete vena cava exclusion. Type 1 hepatic artery anatomy was found both in the donor and the recipient, the gastroduodenal artery was ligated. During the first eight postoperative days, clinical and analytical evolution was satisfactory and Doppler ultrasound showed no abnormalities. On the ninth postoperative day, the patient developed hypovolemic shock due to bleeding at the hepatic artery anastomosis, surgical reconstruction was performed. Postoperative color Doppler showed absent hepatic artery flow and an angiography suggested celiac artery compression. The patient was explored again the same day, liberating the celiac artery from the median arcuate ligament and performing thrombectomy and reconstruction of the hepatic artery anastomosis. The patient made a satisfactory recovery and color Doppler showed adequate flow in the hepatic artery. She is alive, free of biliary complications and enjoying a good quality of life 12 months after transplantation. Conclusion. Median arcuate ligament celiac artery compression is an infrequent anatomical variant that should be intentionally evaluated in the recipient at the time of arterial reconstruction in OLT and specifically be considered in early HAT to allow recognition and effective correction.

  • Acute and fulminant hepatitis induced by flutamide: Case series report and review of the literature Javier Brahm, Magdalena Brahm, Roberto Segovia, Ricardo Latorre, Rodrigo Zapata, Jaime Poniachik, Erwin Buckel, Luis Contreras Page 93-98

    Flutamide is a non-steroidal anti-androgenic drug, commonly used in the treatment of advanced prostate cancer, acne and hirsutism. This drug may induce various degrees of liver injury, including acute liver failure (ALF), with further need for liver transplantation. Here, we present a report of 10 consecutive patients seen in a period of 14 years, with acute liver toxicity induced by flutamide (in most cases severe hepatotoxicity): 3 men and 7 women, with a mean age of 75 and 29 years old, respectively. All men received flutamide as treatment of advanced prostate carcinoma and they developed hepatotoxicity without ALF, and three months after withdrawal of the drug, they recovered completely. In contrast, in 7 young female with liver toxicity caused by flutamide as treatment of various hyperandrogenic conditions (acne and hirsutism), ALF was observed in 5 patients, all of them requiring urgent liver transplantation, with excellent outcome and survival in 4 of them. Based on the above, we believe that flutamide treatment should be preferentially avoided in young female patients with benign pathologies, or if it is used, patients should be warned of its potential severe complications. Also, serial liver tests should be closely monitored and, in case of elevations, the drug should be immediately withdrawn.

  • Thalidomide for the treatment of metastatic hepatic epithelioid hemangioendothelioma: A case report with a long term follow-up Felipe Salech, Sebastián Valderrama, Bruno Nervi, Juan-Carlos Rodriguez, Danny Oksenberg, Alvaro Koch, Gladys Smok, Ignacio Duarte, Rosa María Pérez-Ayuso, Nicolás Jarufe, Jorge Martínez, Alejandro Soza, Marco Arrese, _ Riquelme Page 99-102

    Hepatic epithelioid hemangioendothelioma (HEH) is an unusual, low-grade malignant vascular tumor of the liver. Here we describe a case of a 40-year-old woman who presented with abdominal pain in the upper right quadrant and giant hepatomegaly, in which imaging studies and a fine-needle liver biopsy confirmed the presence of a large EHE with an isolated lung metastasis. After balancing all possible therapeutic modalities the patient was treated conservatively with thalidomide (300 mg/day). The drug was well tolerated with minimal toxicity and the patient continues on therapy 109 months after treatment was started with no disease progression. Current therapeutic options for HEH are discussed in light of the clinical case with particular emphasis on anti-angiogenic therapies.

LETTER TO EDITOR

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