Silva MF, Sapisochin G, Strasser SI, et al.
Liver resection and transplantation offer similar 5-year survival for Child-Pugh-Turcotte A HCC-patients with a single nodule up to 5 cm: a multicenter, exploratory analysis.
Eur J Surg Oncol. 2013; 39(4):386-95 [PubMed]

BACKGROUND AND AIM: The current guideline of the American Association for the Study of Liver Diseases recommends liver resection for Child-Pugh-Turcotte A patients with a single hepatocellular carcinoma, total serum bilirubin ≤ 1 mg/dL and absence of significant portal hypertension. This subset of patients would have a long-term survival comparable to transplantation. The main aim of this study is to evaluate the survival rates in patients with a single nodule ≤ 5 cm following resection.
METHODS: Medical records of 105 Child-Pugh-Turcotte A patients who underwent liver resection between 1997 and 2009 were analyzed in 3 countries.
RESULTS: One, 3-, and 5-year survival rate was 97%, 83%, and 66%, respectively, and no variable that can be assessed prior to liver resection predicted survival probabilities.
CONCLUSIONS: Liver resection offers 5-year survival similar to transplantation for Child-Pugh-Turcotte A patients with hepatocellular carcinoma and a single nodule up to 5 cm, independently of any patient baseline characteristics.

Hsu HY, Chang MH, Ni YH, et al.
Long-term follow-up of children with postnatal immunoprophylaxis failure who were infected with hepatitis B virus surface antigen gene mutant.
J Infect Dis. 2013; 207(7):1047-57 [PubMed]

BACKGROUND: The long-term evolution and outcomes of infection with a hepatitis B virus (HBV) surface antigen (HBsAg) gene mutant (hereafter, "HBsAg-mutant HBV") among immunized children remain unclear.
METHODS: Ninety-five HBsAg-positive children aged 0.5-18.4 years (mean age, 5.8 years) who did not respond to postnatal immunoprophylaxis were prospectively followed for 1-22.8 years (mean follow-up, 8.5 years). Clinical, serologic, and virologic features were compared between 38 untreated HBV e antigen (HBeAg)-positive children carrying HBsAg-mutant HBV (group 1) and 49 children carrying wild-type HBV (group 2). HBsAg-mutant HBV was examined in 20 immunized children presenting with HBV-related hepatocellular carcinoma (HCC).
RESULTS: The initial alanine aminotransferase (ALT) level, the maximal ALT level during the HBeAg-positive phase of HBV infection, the cumulative incidence of HBeAg seroconversion (P = .0018), and the rate of low serum HBV DNA load (defined as <10 copies/mL) at the last visit (P = .006) were higher in group 1 than in group 2. A higher frequency of HBV genotype C and a higher ALT level during surface mutant viremia were observed in codon 110-129 mutants than in codon 144-145 mutants. None of the 95 patients developed cirrhosis or HCC. HBsAg-mutant HBV was detected in 3 of 8 (38%) HBV DNA-positive children with HCC.
CONCLUSIONS: HBeAg-positive immunized children carrying HBsAg-mutant HBV may develop hepatitis activity, HBeAg seroconversion, and a low viremic state earlier than those carrying wild-type HBV. Continuous monitoring of children with wild-type HBV infection and those with HBsAg-mutant HBV for possible development of HCC is needed.

Semeraro M, Branchereau S, Maibach R, et al.
Relapses in hepatoblastoma patients: clinical characteristics and outcome--experience of the International Childhood Liver Tumour Strategy Group (SIOPEL).
Eur J Cancer. 2013; 49(4):915-22 [PubMed]

PURPOSE: To analyse the clinical characteristics and outcome of hepatoblastoma (HB) patients who relapsed after enrolment on SIOPEL studies 1-3.
PATIENTS AND METHODS: Analysis of clinical data of all 59 patients (pts) registered in SIOPEL 1-3 studies, who relapsed after achieving complete remission (CR).
RESULTS: The median time from the initial diagnosis to relapse was 12 months (4-115 m). The site of relapse was lung N=27, liver N=21, both liver and lung N=5 and other N=5 (missing data-MD: 1 patient). All but 9 pts had an alpha-fetoprotein level >10 ng/mL at the time of relapse. Treatment of the relapse included chemotherapy and surgery N=25, chemotherapy alone N=21, surgery alone N=7 and only palliative treatment N=5 (MD: 1 pt). Overall, 31 pts (52%) achieved a second CR. With a median follow-up of 83 months, 23 pts are alive, (18 in 2nd CR, 5 after a second relapse) and 36 pts have died (35 from disease and 1 from complications). Three-year event-free survival and overall survival are 34% and 43% respectively (95% confidence interval [CI] 0.28-0.69). The main factors associated with a good outcome were PRETEXT group I-III at diagnosis, a high AFP level at relapse and relapse treatment including both chemotherapy and surgery.
CONCLUSION: Relapses in HB are rare events occurring in less than 12% of pts after CR. Combined treatment with chemotherapy and surgical removal of the tumour is essential for long-term survival.

Chen X, Zhai J, Cai X, et al.
Severity of portal hypertension and prediction of postoperative liver failure after liver resection in patients with Child-Pugh grade A cirrhosis.
Br J Surg. 2012; 99(12):1701-10 [PubMed]

BACKGROUND: Patients with Child-Pugh grade A cirrhosis and clinical evidence of portal hypertension are likely to develop posthepatectomy liver failure (PHLF). Whether such patients are suitable candidates for partial hepatectomy is controversial. This study explored the impact of portal venous pressure (PVP) on PHLF and the possibility of stratifying patients with Child-Pugh grade A cirrhosis for risk of PHLF using clinical data alone.
METHODS: Between April 2009 and May 2011, consecutive patients who underwent partial hepatectomy for hepatocellular carcinoma and intraoperative measurement of PVP were included in this prospective study. Using signs of clinically significant portal hypertension (CSPH), patients with Child-Pugh grade A cirrhosis were subclassified into three groups: no, mild and severe CSPH. Risk factors for PHLF were subjected to univariable and multivariable analysis, and receiver operating characteristic (ROC) curve analysis.
RESULTS: Sixty-seven (35·3 per cent) of 190 patients developed PHLF, which was persistent in 12 patients (6·3 per cent). Four patients (2·1 per cent) died from PHLF within 3 months of surgery. Multivariable analysis showed both PVP and CSPH to be independent predictors of PHLF (P < 0·001). PVP values, incidence of PHLF and persistent PHLF were significantly higher in the severe CSPH group than in the other two groups (P < 0·001). Severe CSPH (odds ratio 27·68, P = 0·005) and a preoperative neutrophil : lymphocyte ratio (NLR) of 2·8 or above (odds ratio 49·75, P = 0·002) were independent factors affecting the incidence of persistent PHLF.
CONCLUSION: The severity of CSPH, corresponding to different PVP levels, could be used to stratify patients with Child-Pugh grade A cirrhosis and to predict the incidence of PHLF. Patients with severe CSPH or a NLR of 2·8 or above were more likely to develop persistent PHLF after partial hepatectomy.

Dhooge M, Coriat R, Mir O, et al.
Feasibility of gemcitabine plus oxaliplatin in advanced hepatocellular carcinoma patients with Child-Pugh B cirrhosis.
Oncology. 2013; 84(1):32-8 [PubMed]

PURPOSE: Sorafenib improves survival in advanced hepatocellular carcinoma (HCC), but the demonstration of its efficacy and safety is limited to Child-Pugh A cirrhotic patients. The biweekly combination of gemcitabine and oxaliplatin (GEMOX) is safe and widely used in patients with advanced malignancies. We aimed to evaluate the feasibility of GEMOX in HCC patients with Child-Pugh B cirrhosis ineligible for sorafenib.
METHODS: The medical records of cirrhotic patients with advanced HCC receiving the GEMOX regimen between July 2006 and November 2011 were retrospectively reviewed. Treatment was repeated every 2 weeks until disease progression or unacceptable adverse effects occurred. The primary evaluation criterion was safety. Secondary evaluation criteria were the presence of muscle wasting (sarcopenia), response rate, progression-free survival and overall survival (OS).
RESULTS: Patients with Child-Pugh A (group A, n = 17) or Child-Pugh B cirrhosis (group B, n = 15) received a total of 169 cycles (median 4, range 1-16/patient). Eight patients in each group had sarcopenia. Common toxicities were thrombocytopenia (25 and 14 in groups A and B, respectively; p = 0.65) and peripheral neuropathy (44 and 54% in groups A and B, respectively; p = 1). Neither febrile neutropenia nor toxic death occurred. One patient in each group experienced grade 3 oesophageal varices bleeding. The response and disease control rates were 18% (95% CI 0-35.8) and 58.8% (95% CI 35.4-82.2) in group A, and 27% (95% CI 4.3-49.1) and 60.0% (95% CI 35.2-84.8) in group B. The median progression-free survival and OS did not differ between the two groups, but median OS was significantly shorter in sarcopenic patients.
CONCLUSIONS: The GEMOX regimen appears feasible in HCC patients with Child-Pugh B cirrhosis and exerts anti-tumour activity. These data need to be confirmed in a prospective study.

Miyaki D, Aikata H, Honda Y, et al.
Hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma according to Child-Pugh classification.
J Gastroenterol Hepatol. 2012; 27(12):1850-7 [PubMed]

BACKGROUND AND AIM: We compared the treatment response, survival, and safety to hepatic arterial infusion chemotherapy (HAIC) in patients with advanced hepatocellular carcinoma (HCC) according to Child-Pugh (CP) score.
METHODS: The study subjects were 249 patients with advanced HCC and CP class A and B who had been treated with HAIC. Patients were grouped according to CP score (5/6, 7 and 8/9) and their tumor response, tolerance, and survival were assessed.
RESULTS: The median survival time (MST) was 8.2, 9.7, 6.3, and 3.9 months for the whole group, patients with CP 5/6, 7 and 8/9, respectively (P < 0.0001). Complete response (CR) and partial response (PR) were seen in 11 and 57 patients, respectively, with an overall response rate of 27.3%. The response rate was higher in patients with CP score 5/6 and 7, than CP 8/9 (30.5%, 28.2%, 13.8%). The dropout rate was significantly higher in patients with CP score 8/9 than the other two (8.0%, 12.8%, 33.3%, respectively). The survival rate was significantly better in patients who achieved CR/PR than the others with CP score 5/6, 7. CP score 8/9 was an independent negative factor for response and survival.
CONCLUSION: Advanced HCC patients with CP score of 5/6 and 7 showed a better response to HAIC and better prognosis than those with CP score 8/9.

Fricchione MJ, Glenn N, Follmer R, Kent PM
Life-threatening paraneoplastic syndrome in a child with sarcoma of the liver cured by emergency resection.
J Pediatr Hematol Oncol. 2013; 35(2):153-5 [PubMed]

We believe this to be the first case of life-threatening paraneoplastic syndrome (PNS) in a child with undifferentiated embryonal sarcoma of the liver (UESL). We report a case of a 9-year-old child with UESL believed to be unresectable at presentation, who experienced life-threatening, refractory long QTc syndrome, Torsades de pointes, fevers of unknown origin, and secretory diarrhea necessitating emergency surgery. After failure of intravenous immunoglobulin and high-dose steroids to control PNS and despite pancytopenia from chemotherapy, very aggressive surgical resection was life saving and led to rapid resolution of PNS.

Mateos ME, López-Laso E, Pérez-Navero JL, et al.
Successful response to cidofovir of adenovirus hepatitis during chemotherapy in a child with hepatoblastoma.
J Pediatr Hematol Oncol. 2012; 34(7):e298-300 [PubMed]

BACKGROUND: Adenoviral infections are endemic in the pediatric population. Most of these infections are mild and self-limited in immunocompetent individuals. Although in profoundly immunocompromised hosts after solid organ or stem cell transplantation, adenovirus may cause fulminant hepatitis or other life-threatening infections, this is a rare complication in patients receiving standard chemotherapy.
OBSERVATION: We report a case of severe adenovirus hepatitis in a 7-month-old child receiving induction chemotherapy for hepatoblastoma who fully recovered after treatment with cidofovir.
CONCLUSIONS: To our knowledge, this is the first report documenting recovering of severe adenoviral hepatitis in a nontransplanted immunocompromised host.

Zsíros J, Brugières L, Brock P, et al.
Efficacy of irinotecan single drug treatment in children with refractory or recurrent hepatoblastoma--a phase II trial of the childhood liver tumour strategy group (SIOPEL).
Eur J Cancer. 2012; 48(18):3456-64 [PubMed]

PURPOSE: To assess the clinical activity of irinotecan as single drug in children with refractory or recurrent hepatoblastoma.
PATIENTS AND METHODS: Four cycles of irinotecan were administered (20mg/m(2)/day intravenous (i.v.) infusion on days 1-5 and 8-12, every 21days) unless tumour progression occurred or resectability was achieved earlier. Tumour response was assessed according to modified SIOPEL and Response Evaluation Criteria In Solid Tumours (RECIST) criteria. Main end-points were best overall response rate (RR), early progression rate (EPR) and progression free survival (PFS).
RESULTS: Twenty-four eligible patients (median age 58.0months; 19 boys) were enrolled in the study (11 relapses, 13 refractory diseases). Of the 23 evaluable patients six had an overall partial response, 11 stable disease and six progressive disease, of which four were early progression (RR: 26%, EPR: 17%). In eight patients the residual tumour could be completely resected; seven patients became tumour free. At last follow-up 12 patients were alive (six with no evidence of disease, six with disease). PFS at 1year was 24%. Patients with relapse had a higher RR than patients with refractory disease (46% versus 8%) and patients with isolated lung lesions showed a better response than patients with other tumour localisations (50% versus 13%). The main grade 3-4 toxicities, diarrhoea and neutropenia, occurred in half of the patients.
CONCLUSION: Irinotecan has a significant anti-tumour activity and acceptable toxicity in patients with relapsed hepatoblastoma and therefore should be considered for the treatment of these patients. Exploration of the role of irinotecan in the initial treatment of hepatoblastoma is warranted.

Tsai J, Mattei P
Median sternotomy for bilateral pulmonary metastasectomy in children.
J Pediatr Surg. 2012; 47(7):1345-8 [PubMed]

BACKGROUND: Complete resection of metastatic pulmonary nodules in some children may increase survival. We present a series of 16 children who underwent median sternotomy for bilateral pulmonary metastasectomy from January 1, 1999, to December 31, 2010.
METHODS: We reviewed the records of 16 children (3-18 years old, 12 boys, 4 girls) with bilateral pulmonary metastases who underwent median sternotomy with the intent of curative resection. All were treated with alternating single-lung ventilation and careful bilateral manual palpation for nodules.
RESULTS: The mean number of lesions resected was 11.6 (range, 2-33). Two patients who were found to have lesions that were too numerous to count underwent biopsy only. There were no major complications, and median length of hospital stay was 4 days. One patient had postoperative atelectasis, and another had an air leak; both were discharged on the fifth postoperative day. Seven patients have since died, 2 of whom underwent further resection for recurrent disease, with a median survival of 30 months. Nine patients are currently alive with a median follow-up of 30 months, 2 of whom have recurrent disease.
CONCLUSIONS: Median sternotomy allows excellent exposure of both lungs. In our series, there were no lesions that could not be resected because of inadequate exposure, including several in the left lower lobe posteriorly, and most patients were discharged within 4 days without major complications. In children with metastatic lung disease, median sternotomy is safe and avoids treatment delay and a second operation.

Ismail H, Broniszczak D, Kaliciński P, et al.
Changing treatment and outcome of children with hepatoblastoma: analysis of a single center experience over the last 20 years.
J Pediatr Surg. 2012; 47(7):1331-9 [PubMed]

BACKGROUND/PURPOSE: The aim of the study was to analyze changing management and survival of children with hepatoblastoma (HBL) treated in one center.
MATERIALS AND METHODS: Over the last 20 years, 51 children with HBL were treated. Surgery was performed in 48 children (94.1%), conventional liver resection in 38 (of those, 2 received a rescue liver transplantation [LTx] for relapse), and total hepatectomy and primary LTx in 10 patients. The remaining 3 patients received only palliative treatment. Patient data were analyzed for survival with respect to PRETreatment EXTent of disease (PRETEXT), metastases, histopathology, conventional resection, and LTx.
RESULTS: Survival of children with HBL treated with liver resection is 71% and 80% for primary LTx. Favorable prognostic factors for patient survival was tumor histology as epithelial-fetal subtype and mixed epithelial and mesenchymal type, without teratoid features, and good response to chemotherapy (necrosis, fibrosis). Unfavorable prognostic factors were small cells undifferentiated, transitional liver cell tumor, α-fetoprotein level above 1,000,000 IU/mL and below 100 IU/mL at diagnosis, lung metastases, and local recurrence after initial resection. Survival was related to PRETEXT stage. However, among patients with PRETEXT III and IV, LTx resulted in better survival.
CONCLUSION: Liver transplantation is a good option for children with advanced HBL. Early referral of children with potentially unresectable tumors to centers where combined treatment (chemotherapy, surgery including LTx) is available is crucial.

Kalapurakal JA, Pokhrel D, Gopalakrishnan M, Zhang Y
Advantages of whole-liver intensity modulated radiation therapy in children with Wilms tumor and liver metastasis.
Int J Radiat Oncol Biol Phys. 2013; 85(3):754-60 [PubMed]

PURPOSE: To demonstrate the dosimetric advantages of intensity modulated radiation therapy (IMRT) in children with Wilms tumor (WT) undergoing whole-liver (WL) RT.
METHODS AND MATERIALS: Computed tomography simulation scans of 10 children, either 3 (3D) or 4-dimensional (4D), were used for this study. The WL PTV was determined by the 3D or 4D liver volumes, with a margin of 1 cm. A total of 40 WL RT plans were performed: 10 each for left- and right-sided WT with IMRT and anteroposterior-posteroanterior (AP-PA) techniques. The radiation dose-volume coverage of the WL planning target volume (PTV), remaining kidney, and other organs were analyzed and compared.
RESULTS: The 95% dose coverage to WL PTV for left and right WT were as follows: 97% ± 4% (IMRT), 83% ± 8% (AP-PA) (P<.01) and 99% ± 1% (IMRT), 94% ± 5% (AP-PA) (P<.01), respectively. When 3D WL PTV was used for RT planning, the AP-PA technique delivered 95% of dose to only 78% ± 13% and 88% ± 8% of 4D liver volume. For left WT, the right kidney V15 and V10 for IMRT were 29% ± 7% and 55% ± 8%, compared with 61% ± 29% (P<.01) and 78% ± 25% (P<.01) with AP-PA. For right WT, the left kidney V15 and V10 were 0 ± 0 and 2% ± 3% for IMRT, compared with 25% ± 19% (P<.01) and 40% ± 31% (P<.01) for AP-PA.
CONCLUSIONS: The use of IMRT and 4D treatment planning resulted in the delivery of a higher RT dose to the liver compared with the standard AP-PA technique. Whole-liver IMRT also delivered a significantly lower dose to the remaining kidney.

Smith EA, Salisbury S, Martin R, Towbin AJ
Incidence and etiology of new liver lesions in pediatric patients previously treated for malignancy.
AJR Am J Roentgenol. 2012; 199(1):186-91 [PubMed]

OBJECTIVE: The purpose of this study was to retrospectively evaluate the time course, cause, and imaging characteristics of all new liver lesions in pediatric patients with a previously treated malignancy.
MATERIALS AND METHODS: Our hospital cancer registry was used to identify patients between 1980 and 2005 who met the following criteria: solid tumor, survival > 2 years after diagnosis, no liver lesions at a posttreatment baseline, and cross-sectional imaging follow-up of > 2 years. Final dictated reports of all cross-sectional imaging examinations including the abdomen were reviewed for any mention of new liver lesions. Positive reports were followed by consensus review of the images and clinical data. Patients were divided into three groups: those with suspected or proven focal nodular hyperplasia (FNH), those with suspected or proven metastases, and those with other lesions. An exact Wilcoxon test was used to evaluate the differences between the groups.
RESULTS: Of 967 patients who met the initial inclusion criteria, 273 had adequate follow-up to be included in the study. Forty-six patients (16.8%) developed new liver lesions during the study period, and 14 of those 46 were classified into the FNH group (30.4%) and seven were classified into the metastasis group (15.2%). A significant difference was found in the median time to the development of FNH versus metastasis and other lesions (FNH, 92.9 months; metastasis, 43.2 months; other lesions, 18.5 months; p < 0.0001). A significant difference was also seen in the median length of follow-up between the groups (FNH, 115.6 months; metastasis, 57 months; other lesions, 50.8 months; p = 0.002). The imaging features of the groups also differed.
CONCLUSION: The most common liver lesion encountered in pediatric patients previously treated for malignancy was FNH, which occurred farther from the time of diagnosis and had different imaging characteristics from both metastases and other liver lesions.

Lee MH, Yoo SY, Kim JH, et al.
Hypervascular hepatic nodules in childhood cancer survivors: clinical and imaging features.
Clin Imaging. 2012 Jul-Aug; 36(4):301-7 [PubMed]

AIM: The aim was to review the clinical and imaging features of hypervascular hepatic nodule (HHN) in childhood cancer survivors.
MATERIALS AND METHODS: We retrospectively reviewed 11 pediatric patients (female:male, 7:4; age range, 4.0-12.3 years) who had HHNs detected by surveillance computed tomography (CT) after treatment of a malignant solid tumor and subsequently followed by serial imaging without evidence of recurrent malignancy. The lesions were analyzed in terms of number, size, location, CT and ultrasonographic (US) features, and changes in background liver. In addition, clinical features were investigated along with follow-up changes of HHNs by imaging monitoring.
RESULTS: Time between initial diagnosis of malignancy and HHN occurrence ranged from 3.2 to 8.5 years (median, 5.8 years). Ten patients had received high-dose chemotherapy and autologous stem cell transplantation for advanced neuroblastoma. A total of 22 nodules were detected, being multiple in six patients and measuring 0.5-3.0 cm in size. At sequential postcontrast CT, nodules demonstrated moderate to strong enhancement during the earlier phase and were isoattenuated during the later phase. On US, they appeared as hypo- or isoechoic lesions. During follow-up, 11 nodules (50%) regressed, 6 (27%) progressed, and 5 (23%) remained stable. Additional HHNs were noted in four patients during follow-up.
CONCLUSION: Childhood cancer survivors are at risk of developing HHNs, which are often multiple and small, years after completing chemotherapy. They are nonaggressive and tend to have a benign course, making conservative management reasonable.

Alaggio R, Cecchetto G, Martignoni G, et al.
Malignant perivascular epithelioid cell tumor in children: description of a case and review of the literature.
J Pediatr Surg. 2012; 47(6):e31-40 [PubMed]

Perivascular epithelioid cell tumors (PEComas) include different morphological entities originating from perivascular epithelioid cells. Their clinical behavior is not predictable, and there are no strict histologic criteria for malignancy, although larger tumors with infiltrative growth, hypercellularity, cellular atypia, atypical mitoses, and necrosis generally have a malignant course. Pediatric PEComas are rare, with less than 40 cases reported, mostly in children older than 5 years. We describe a case of malignant PEComa of the ligamentum teres in a 2-year-old girl, characterized by the occurrence of local relapse after primary treatment with chemotherapy and surgery and poor response to imatinib mesilate and temsirolimus used after further analyses confirmed p70S6K expression involved in the mTOR pathway. The girl was eventually treated with a debulking surgical procedure and is now alive with disease 6 years after diagnosis. Literature data of children affected by PEComas were also analyzed, trying to identify pathologic characteristics that could predict their course and therapeutic options. Histologically, they may be differentiated in 3 prognostic categories: (1) benign, lacking unfavorable morphological markers; (2) with uncertain malignant potential, carrying 1 unfavorable marker; and (3) malignant, with at least 2 unfavorable markers. In the literature, 9% of cases occurred as a second malignancy probably because of genomic instability related to treatment. Their different biology and the potential value of targeted therapies remain to be explored. The indolent evolution in our patient was similar to that reported in some other cases in the literature. In terms of treatment, the present case suggests a minor response to temsirolimus compared with the adult population.

Sanchez SE, Javid PJ, Lao OB, et al.
Hepatic artery thrombosis and liver malignancy in pediatric liver transplantation.
J Pediatr Surg. 2012; 47(6):1255-60 [PubMed]

BACKGROUND: Hepatic artery thrombosis (HAT) remains a significant cause of graft failure and mortality after pediatric liver transplantation. Conditions not associated with hepatic failure, such as liver tumors, may be more prone to thrombotic problems after transplant. We hypothesized that liver transplant for hepatic malignancies may be associated with increased rates of HAT in the posttransplant period.
METHODS: We conducted a retrospective review of pediatric patients (age, 0-21 years) who underwent primary liver transplantation at a free-standing children's hospital from 1990 to 2009. We reviewed cause of underlying liver disease, age, sex, weight, occurrence of HAT, use of antiplatelets and anticoagulants perioperatively, as well as reintervention, retransplant, and death.
RESULTS: A total of 129 children underwent 146 liver transplants, and 15 (12%) patients developed HAT. Nine liver transplants were performed for hepatic malignancy, and 4 (44%) of these patients developed HAT (relative risk, 4.85; 95% confidence interval, 1.9-12.2; P = .0015). All 4 children with hepatic malignancy and HAT required reintervention, including 3 retransplants (75%). One of these patients died.
CONCLUSIONS: Hepatic artery thrombosis occurs approximately 5 times more often and appears to be more morbid in children with hepatic malignancy after transplantation. Prospective evaluation of prophylactic anticoagulation regimens in the setting of hepatic malignancy requiring transplantation is warranted.

Ovchinsky N, Moreira RK, Lefkowitch JH, Lavine JE
Liver biopsy in modern clinical practice: a pediatric point-of-view.
Adv Anat Pathol. 2012; 19(4):250-62 [PubMed] Article available free on PMC after 01/07/2013

Liver biopsy remains the foundation of evaluation and management of liver disease in children, although the role of the liver biopsy is changing with development of alternative methods of diagnosis and advancement of hepatic imaging techniques. The indications for liver biopsy are evolving as current knowledge of etiologies, noninvasive biomarker alternatives, and treatment options in pediatric liver disease are expanding. The procedure can often be complicated in children by technical difficulties, cost, and smaller specimen size. Communication and partnership of clinicians with pathologists experienced in pediatric liver diseases are essential. DNA sequencing, novel imaging modalities, noninvasive biomarkers of fibrosis and apoptosis, proteomics, and genome-wide association studies offer potential alternative methods for evaluation of liver disease in children. This review presents specific indications, considerations, methods, complications, contraindications, and alternatives for pediatric liver biopsy.

Lin ZZ, Hsu C, Hu FC, et al.
Factors impacting prognosis prediction in BCLC stage C and Child-Pugh class A hepatocellular carcinoma patients in prospective clinical trials of systemic therapy.
Oncologist. 2012; 17(7):970-7 [PubMed] Article available free on PMC after 01/07/2013

BACKGROUND: The purpose of this study was to determine the prognostic significance of clinical factors and staging systems for survival of hepatocellular carcinoma (HCC) patients who are candidates for therapeutic clinical trials.
METHODS: From December 1990 to July 2005, 236 patients with unresectable HCC were enrolled into six published phase II trials assessing various therapeutic regimens. Of these, 156 chemotherapy-naive patients with Child-Pugh class A and Barcelona Clinic Liver Cancer stage C disease were included in this analysis. Twenty-seven relevant clinical characteristics were analyzed to identify prognostic factors of survival. Beyond these prognosticators, the predictive ability of eight staging systems (the tumor-node-metastasis, Okuda, Cancer of the Liver Italian Program [CLIP], Chinese University Prognostic Index, Japanese Integrated Staging, Tokyo, National Taiwan University Risk Estimation, and Advanced Liver Cancer Prognostic System [ALCPS] score) were compared using the Akaike information criteria.
RESULTS: The median overall survival time was 129 days (95% confidence interval, 111-147 days). Significant predictors of a shorter overall survival time were an Eastern Cooperative Oncology Group performance status score ≥2, the presence of symptoms, ascites, an aspartate transaminase level more than two times the upper limit of normal, and regional lymph node involvement. The ALCPS and CLIP scores were superior to the other systems for predicting survival.
CONCLUSIONS: The prognosis of patients with advanced HCC who are candidates for therapeutic clinical trials is affected by several factors related to the patient, liver function, and the tumor. The ALCPS and CLIP scores appear to be superior to the other systems for predicting survival.

Cheung TT, Chan SC, Chok KS, et al.
Rapid measurement of indocyanine green retention by pulse spectrophotometry: a validation study in 70 patients with Child-Pugh A cirrhosis before hepatectomy for hepatocellular carcinoma.
Hepatobiliary Pancreat Dis Int. 2012; 11(3):267-71 [PubMed]

BACKGROUND: The indocyanine green (ICG) retention test is the most popular liver function test for selecting patients for major hepatectomy. Traditionally, it is done using spectrophotometry with serial blood sampling. The newly-developed pulse spectrophotometry is a faster alternative, but its accuracy on Child-Pugh A cirrhotic patients undergoing hepatectomy for hepatocellular carcinoma has not been well documented. This study aimed to assess the accuracy of the LiMON(®), one of the pulse spectrophotometry systems, in measuring preoperative ICG retention in these patients and to devise an easy formula for conversion of the results so that they can be compared with classical literature records where ICG retention was measured by the traditional method.
METHODS: We measured the liver function of 70 Child-Pugh A cirrhotic patients before hepatectomy for hepatocellular carcinoma from September 2008 to January 2009. ICG retention at 15 minutes measured by traditional spectrophotometry (ICGR15) was compared with ICG retention at 15 minutes measured by the LiMON (ICGR15(L)).
RESULTS: The median ICGR15 was 14.7% (5.6%-32%) and the median ICGR15(L) was 10.4% (1.2%-28%). The mean difference between them was -4.3606. There was a strong correlation between ICGR15 and ICGR15(L) (correlation coefficient, 0.844; 95% confidence interval, 0.762-0.899). The following formula was devised: ICGR15=1.16XICGR15(L)+2.73.
CONCLUSIONS: The LiMON provides a fast and repeatable way to measure ICG retention at 15 minutes, but with constant underestimation of the real value. Therefore, when comparing results obtained by traditional spectrophotometry and the LiMON, adjustment of results from the latter is necessary, and this can be done with a simple mathematical calculation using the above formula.

Armeanu-Ebinger S, Wenz J, Seitz G, et al.
Characterisation of the cell line HC-AFW1 derived from a pediatric hepatocellular carcinoma.
PLoS One. 2012; 7(5):e38223 [PubMed] Article available free on PMC after 01/07/2013

Current treatment of paediatric hepatocellular carcinoma (HCC) is often inefficient due to advanced disease at diagnosis and resistance to common drugs. The aim of this study was to generate a cell line derived from a paediatric HCC in order to expand research in this field. We established the HC-AFW1 cell line from a liver neoplasm of a 4-year-old boy through culturing of primary tumor specimens. The cell line has been stable for over one year of culturing and has a doubling time of 40 h. The tumour cells have an epithelial histology and express HCC-associated proteins such as Alpha-fetoprotein (AFP), Glypican 3, E-cadherin, CD10, CD326, HepPar1 and Vimentin. Forty-nine amino acids in exon 3 of β-Catenin that involve the phosphorylation sites of GSK3 were absent and β-Catenin is detectable in the cell nuclei. Cytogenetic analysis revealed large anomalies in the chromosomal map. Several alterations of gene copy numbers were detected by genome-wide SNP array. Among the different drugs tested, cisplatin and irinotecan showed effective inhibition of tumour cell growth in a proliferation assay at concentrations below 5 µg/ml. Subcutaneous xenotransplantation of HC-AFW1 cells into NOD/SCID mice resulted in fast growing dedifferentiated tumours with high levels of serum AFP. Histological analyses of the primary tumour and xenografts included national and international expert pathological review. Consensus reading characterised the primary tumour and the HC-AFW1-derived tumours as HCC. HC-AFW1 is the first cell line derived from a paediatric HCC without a background of viral hepatitis or cirrhosis and represents a valuable tool for investigating the biology of and therapeutic strategies for childhood HCC.

López-Terrada D, Zimmermann A
Current issues and controversies in the classification of pediatric hepatocellular tumors.
Pediatr Blood Cancer. 2012; 59(5):780-4 [PubMed]

Systematic histopathologic examination of hepatoblastoma specimens from patients enrolled in therapeutic protocols has allowed the identification of clinically relevant histologic subtypes that are being incorporated into risk stratification systems. Genetic and molecular studies have documented recurrent chromosomal abnormalities and aberrant activation of developmental, and oncogenic signaling pathways in hepatoblastoma. Molecular profiling has also identified molecular subclasses and gene signatures that could be used to stratify hepatoblastoma patients. Future international collaboration is needed to develop consensus pathology classifications, and to progressively incorporate genetic and molecular biomarkers into therapeutic pediatric liver tumors protocols.

Zachau L, Zeckey C, Schlue J, et al.
Haematogenous abdominal wall metastasis of differentiated, alpha-fetoprotein-negative hepatocellular carcinoma after previous antiandrogen therapy within a site of lipoma manifestation since childhood.
World J Surg Oncol. 2012; 10:98 [PubMed] Article available free on PMC after 01/07/2013

BACKGROUND: Cases with subcutaneous metastasis of differentiated hepatocellular carcinoma to the abdominal wall without prior seeding as a consequence of local interventions with a negative or normal alpha-fetoprotein level in the serum are extremely rare.
CASE REPORT: This is the first report of a case with AFP-negative, differentiated hepatocellular carcinoma metastasis to the abdominal wall within a pre-existing subcutaneous lipoma since childhood after antiandrogen therapy with leuprorelin and buserelin acetate for prostate cancer without seeding.
METHODS: Clinical features including histology, immunohistochemistry, clinical course and surgical approach are presented.
RESULTS: Histological examination revealed a hepatocellular carcinoma with a trabecular and pseudoglandular growth pattern with moderately atypical hepatocytes with multifocal bile formation within a lipoma. The postoperative course of abdominal wall reconstruction with a monocryl-prolene mesh and a local flap after potentially curative resection was uncomplicated.
DISCUSSION AND CONCLUSION: It may be that previous antiandrogen treatment for prostate carcinoma contributed to the fact that our patient developed alpha-fetoprotein-negative and androgen receptor-negative subcutaneous abdominal wall metastasis within a pre-existing lipoma since childhood.

Davenport KP, Blanco FC, Sandler AD
Pediatric malignancies: neuroblastoma, Wilm's tumor, hepatoblastoma, rhabdomyosarcoma, and sacroccygeal teratoma.
Surg Clin North Am. 2012; 92(3):745-67, x [PubMed]

Common pediatric malignancies are reviewed: neuroblastoma, Wilms tumor, hepatoblastoma, rhabdomyosarcoma, and sacrococcygeal teratoma. Elements of presentation, diagnosis, staging, treatment, and longterm prognosis are discussed, with particular attention to surgical management.

van As JW, van den Berg H, van Dalen EC
Medical interventions for the prevention of platinum-induced hearing loss in children with cancer.
Cochrane Database Syst Rev. 2012; 5:CD009219 [PubMed]

BACKGROUND: Platinum-based therapy, including cisplatin, carboplatin and/or oxaliplatin, is used to treat a variety of paediatric malignancies. Unfortunately, one of the most important adverse effects is the occurrence of hearing loss or ototoxicity. In an effort to prevent this ototoxicity, different otoprotective medical interventions have been studied.
OBJECTIVES: The primary objective was to assess the efficacy of different otoprotective medical interventions in preventing hearing loss in children with cancer treated with platinum-based therapy. Secondary objectives were to determine possible effects of these interventions on anti-tumour efficacy, toxicities other than hearing loss and quality of life.
SEARCH METHODS: We searched the electronic databases Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 4), MEDLINE (PubMed) (1945 to 22 December 2011) and EMBASE (Ovid) (1980 to 22 December 2011). In addition, we handsearched reference lists of relevant articles and the conference proceedings of the International Society for Paediatric Oncology (2006 to 2011), the American Society of Pediatric Hematology/Oncology (2007 to 2011) and the International Conference on Long-Term Complications of Treatment of Children and Adolescents for Cancer (2010). We scanned the International Standard Randomized Controlled Trial Number (ISRCTN) Register and the National Institute of Health Register for ongoing trials (www.controlled-trials.com) (searched on 20 December 2011).
SELECTION CRITERIA: Randomized controlled trials (RCTs) or controlled clinical trials (CCTs) evaluating platinum-based therapy together with an otoprotective medical intervention versus platinum-based therapy with placebo, no additional treatment or another protective medical intervention in children with cancer.
DATA COLLECTION AND ANALYSIS: Two review authors independently performed the study selection, risk of bias assessment of included studies and data extraction, including adverse effects. Analyses were performed according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions.
MAIN RESULTS: We identified two RCTs and one CCT (total number of patients 149) evaluating the use of amifostine versus no additional treatment. Two studies included children with osteosarcoma, the other study included children with hepatoblastoma. Patients received cisplatin only or a combination of cisplatin and carboplatin, either administered intra-arterially or intravenously. All studies had methodological limitations. Unfortunately, pooling of the results of included studies was not possible. However, in all individual studies no significant difference was identified in symptomatic ototoxicity only (that is grade 2 or higher) and combined asymptomatic and symptomatic ototoxicity (that is grade 1 or higher) between children treated with or without amifostine. Only one study, including children with osteosarcoma treated with intra-arterial cisplatin, provided information on tumour response, defined as the number of patients with a good or partial remission. The 'available data' analysis (data were missing for one patient), 'best case scenario' analysis and 'worst case scenario' analysis all showed a difference in favour of amifostine, but this difference was significant only in the 'worst case scenario' analysis (P = 0.04). No information on survival was available for any of the included study populations. Only one study, including children with osteosarcoma treated with intra-arterial cisplatin, provided data on the number of patients with adverse effects other than ototoxicity grade 3 or higher. There was a significant difference in favour of the control group in the occurrence of vomiting grade 3 or 4 (RR 9.04; 95% CI 1.99 to 41.12; P = 0.004). No significant difference was identified between treatment groups for cardiotoxicity and renal toxicity grade 3 or 4. None of the studies evaluated quality of life. No eligible studies were found for possible otoprotective medical interventions other than amifostine and other types of malignancies.
AUTHORS' CONCLUSIONS: At the moment there is no evidence from individual studies in children with osteosarcoma and hepatoblastoma treated with different platinum analogues and dosage schedules which underscores the use of amifostine as an otoprotective intervention as compared to no additional treatment. Since pooling of results was not possible and all studies had serious methodological limitations, no definitive conclusions can be made. It should be noted that 'no evidence of effect', as identified in this review, is not the same as 'evidence of no effect'. Based on the currently available evidence, we are not able to give recommendations for clinical practice. For other possible otoprotective medical interventions and other types of malignancies no eligible studies were identified, so no conclusions can be made about their efficacy in preventing ototoxicity in children treated with platinum-based therapy. More high quality research is needed.

Emre S, Umman V, Rodriguez-Davalos M
Current concepts in pediatric liver tumors.
Pediatr Transplant. 2012; 16(6):549-63 [PubMed]

Liver tumors in children can be classified into benign or malignant; some of the benign lesions can have the potential of malignant transformation, and therefore the therapeutic approach may change. These neoplasms account for nearly 1-2% of all pediatric tumors and they have gained significant attention in the last decades due to data suggesting that the incidence may be increasing 5% annually. We know that with new and improved imaging modalities some of these lesions may be detected more often than before. Recent studies showed that liver cancer represented 2% of malignancies in infants by 1980s and this was doubled in incidence to 4% in the following 10 yr. In this review our aim is to discuss all primary liver tumors in children with attention to their clinicopathological and immunohistochemical features followed by the current standard of care.

Lacaille F
Liver tumours, toxic hepatitis, intestinal failure-associated liver disease in children.
Clin Res Hepatol Gastroenterol. 2012; 36(3):308-10 [PubMed]

Liver cancers in children are primitive (hepatoblastoma, fibrolamellar hepatocarcinoma, sarcomas), or arise on a genetic or viral disease. Their treatment is a combination of chemotherapy (hepatoblastoma) and surgery. Neonatal hemangioendotheliomas may induce heart failure. They are now successfully treated with propranolol. Focal nodular hyperplasia is the most frequent benign tumour in older children and adolescents. Drug hepatotoxicity is not very frequent. Antipyretic drugs may induce severe side effects. Liver failure due to valproic acid is diagnostic of a respiratory chain disorder. The liver side effects of antituberculous and antiretroviral drugs should be monitored. Intestinal failure-associated liver disease is common and can be prevented or treated. Early referral to a specialized centre is important for the prognosis.

Chiu J, Tang YF, Yao TJ, et al.
The use of single-agent sorafenib in the treatment of advanced hepatocellular carcinoma patients with underlying Child-Pugh B liver cirrhosis: a retrospective analysis of efficacy, safety, and survival benefits.
Cancer. 2012; 118(21):5293-301 [PubMed]

BACKGROUND: This study explored the efficacy, tolerability, and survival benefits of using sorafenib in patients with Child-Pugh class B (CPB) cirrhosis.
METHODS: Patients with advanced hepatocellular carcinoma who were treated with sorafenib at Queen Mary Hospital, Hong Kong, China, were analyzed retrospectively. Treatment outcomes were analyzed according to their respective Child-Pugh status. Patients with CPB disease were further divided into CPB7 (those with a score of 7) and CPB8-9 (a score of 8 or 9) subgroups.
RESULTS: The baseline demographic parameters were comparable between 108 patients with Child-Pugh class A (CPA) disease and 64 CPB patients. Both clinical benefit rate (21.3% vs 32.4% vs 14.8%; P = .23) and progression-free survival (median: 3.2 months vs 3.2 months vs 2.3 months; P = .26) were similar among CPA, CPB7, and CPB8-9 groups, respectively. The overall survival was different among these groups (P = .002) and showed a trend toward worse outcome in CPB patients: the median was 6.1, 5.4, and 2.7 months among CPA, CPB7, and CPB8-9 patients, respectively. The commonest grade 3/4 adverse events were hand-foot syndrome (13.5%), diarrhea (9.9%), and rash (7.0%). Grade 3/4 leukopenia, thrombocytopenia, and anemia occurred in 2.9%, 5.3%, and 8.8% of the patients, respectively. Overall, the 3 groups of patients experienced similar incidence of most of these adverse events. Nonetheless, CPB patients experienced more anemia (P = .01), gastrointestinal bleeding (P = .02), and hepatic encephalopathy (P = .02).
CONCLUSIONS: CPA and CPB patients tolerated sorafenib similarly and derived similar clinical and progression-free survival benefit. Among CPB patients, most benefits were observed in patients with a score of 7. Nevertheless, CPB patients were more susceptible to developing cirrhotic complications, and thus more vigilant surveillance is needed.

George SL, Broster S, Chisholm JC, Brock P
Docetaxel in the treatment of children with refractory or relapsed hepatoblastoma.
J Pediatr Hematol Oncol. 2012; 34(7):e295-7 [PubMed]

We report on the use of single-agent docetaxel (100 mg/m(2) in children >10 kg, 3.3 mg/kg in children <10 kg), given as a 1-hour infusion at 21-day intervals in 5 children with relapsed or refractory hepatoblastoma. One patient achieved complete remission of pulmonary metastases after 2 courses of docetaxel and remains well 10 years later, after completion of 13 courses of docetaxel and whole-lung radiotherapy. One patient showed a partial response to docetaxel based on α-fetoprotein measurements. Docetaxel shows some activity in progressive hepatoblastoma in this small case series and is a potential drug for future study in this disease.

Sanada Y, Urahashi T, Ihara Y, et al.
Liver transplantation for a pediatric patient with hemophilia B.
Pediatr Transplant. 2012; 16(6):E193-5 [PubMed]

Hemophilia exposes patients to greater risks of bleeding complications during the perioperative period. However, there are no current protocols for factor replacement during LT. We herein describe a case of pediatric living donor LDLT performed for a patient with hemophilia B using perioperative short-term factor replacement. A 4-yr-old female patient with an extrahepatic portosystemic shunt and asymptomatic hemophilia B (factor IX activity 18.7%) underwent an ABO-compatible LDLT using a left lobe graft. The bleeding volume was 2980 mL. Freeze-dried human blood coagulation factor IX concentrate (Novact M, Kaketsuken, Japan) was administered at the induction of anesthesia and at the end of LDLT by bolus infusion (80 U/kg) and was continued by bolus infusion (40 U/kg) on POD 1, 2, 3, and 4. On POD 1, 5, 8, and 12, the factor IX plasma levels were 34.5%, 64.9%, 43.5%, and 53.1%, respectively. The postoperative course was uneventful, and the patient is currently doing well at 2.5 yr after LDLT. Factor concentrate should be administered at the induction of anesthesia and at the end of LT by bolus infusion, and thereafter be continued for a few days after LT by bolus infusion.

van Laarhoven S, van Baren R, Tamminga RY, de Jong KP
Radiofrequency ablation in the treatment of liver tumors in children.
J Pediatr Surg. 2012; 47(3):e7-e12 [PubMed]

Hepatoblastoma and liver metastasis of Wilms' tumors are rare hepatic tumors in children. Treatment of both tumors consists of a combination of chemotherapy and liver surgery. Radiofrequency ablation (RFA) is frequently used for the treatment of adult liver tumors but is rarely mentioned as a treatment option in pediatric liver tumors. We present a patient with hepatoblastoma and 1 with liver metastasis from a Wilms' tumor. Both patients were treated according to the latest protocols except that surgery included use of RFA. Both are well and recurrence free 8 and 3 years after surgery. Radiofrequency ablation may be a good addition to the existing arsenal of treatment modalities for pediatric liver tumors.