Novel therapeutic approaches in the treatment of children with hepatoblastoma

Hepatoblastoma is the most common liver tumor diagnosed in children. Children with persistently unresectable disease, metastatic disease at presentation, recurrent disease, or slowly declining alpha-fetoprotein levels are at high risk for recurrence, exhibit an extremely poor prognosis, and are in desperate need of novel therapeutic agents and strategies. Four high-risk patients were treated. One patient with a local recurrence was treated with irinotecan followed by orthotopic liver transplant. Three patients were treated with tandem high-dose chemotherapy (HDT) with autologous stem cell rescue (two with primary metastatic disease and one with recurrent disease). All three of the patients treated with HDT had relapse (two of them subsequently received irinotecan); the remaining patient underwent surgical resection of a solitary recurrent pulmonary metastasis. Irinotecan demonstrated significant antitumor effects in all three treated patients and was well tolerated. None of the three patients treated with HDT remained disease-free, although the patient who underwent surgical resection of a solitary recurrent pulmonary metastasis remains disease-free 6 years from diagnosis. Further exploration of the use of irinotecan is warranted in high-risk patients with hepatoblastoma.     

High-risk surgically resected pediatric melanoma and adjuvant interferon therapy

BACKGROUND: Pediatric patients with high-risk surgically resected melanoma are at risk for relapse, yet little is known about these young patients and how they tolerate high-dose interferon therapy. PROCEDURE: We reviewed medical records of patients (< or =18 years) with high-risk melanoma referred to the University of Michigan Pediatric Hematology-Oncology service between January 1989 and July 2003. RESULTS: Fourteen patients were identified with high-risk resected melanoma. The median age at diagnosis was 8.5 years. The median time to establish diagnosis was 9 months. Primary lesions were diagnosed as unequivocal melanoma, atypical epithelioid melanocytic proliferations, or atypical Spitz tumor with indeterminate malignant potential. Twelve patients had a positive sentinel lymph node (SLN) biopsy or a palpable regional lymph node and underwent regional lymph node dissection (LND). Two patients with unequivocal melanoma with Breslow depth >4 mm had negative SLN biopsies. Twelve patients received adjuvant high-dose interferon. The following toxicities were observed: constitutional symptoms, gastrointestinal symptoms, depression or neuropsychiatric symptoms, myelosuppression, elevated AST or ALT, hypothyroidism, and hypertension. Grade 3 or 4 toxicities were uncommon with exception of neutropenia, resulting in modification of therapy in one patient. All patients are alive and free of disease at follow-up (median 24.5 months). CONCLUSIONS: Invasive melanoma can occur in very young children. Despite early signs of malignancy, there is often a delay in diagnosis. Histologically, diagnosis may be difficult because of overlap with Spitz nevi. Pediatric patients tolerated adjuvant high-dose interferon well and may be less likely than adults to require therapy modification secondary to toxicities.     

Use of sentinel lymph node biopsy and high-dose interferon in pediatric patients with high-risk melanoma: the Hospital for Sick Children experience

BACKGROUND: Melanoma comprises less than 3% of all cancers seen in children. Sentinel lymph node biopsy (SLNBX) is an important predictor of outcome in adult melanoma and has not been widely used in pediatrics. Furthermore, adjuvant interferon has only been rarely used in childhood high-risk disease. OBJECTIVE: To review our experience with high-risk melanoma, the feasibility of SLNBX and the tolerance of high-dose interferon (HDI) therapy. METHODS: We retrospectively reviewed the medical records of patients with the diagnosis of cutaneous melanoma at our center over a 10-year period. RESULTS: Eleven patients were identified (median age of 12 y). Six of 10 patients who underwent SLNBX had disease in the lymph nodes and no complications from this procedure were observed. After complete lymph node dissection in these 6 patients, 1 developed wound infection and 2 had chronic lymph edema. Five patients were treated with adjuvant HDI of whom 2 patients required dose modification due to myelosuppression and liver toxicity. After a median follow-up of 26 months, 10 out of 11 patients are in remission. CONCLUSIONS: SLNBX is feasible and safe in pediatric melanoma and offers the potential to identify patients at high risk for disease progression who could benefit from HDI.     

A phase II trial using thalidomide for Langerhans cell histiocytosis

BACKGROUND: Few new drugs for treatment of Langerhans cell histiocytosis (LCH) have been studied. Tumor necrosis factor-alpha (TNF-alpha) is a prime therapeutic target since it appears to be present in elevated amounts in LCH lesions. Thalidomide inhibits TNF-alpha production by affecting the gene promoter as well as other anti-cytokine effects. PROCEDURES: A Phase II trial of thalidomide for treatment of LCH patients who had failed primary and at least one secondary regimen was conducted. Sixteen patients were enrolled: nine males and seven females ranging in age from 19 months to 45 years. Six patients were high risk (HR) because of spleen, liver, lung, or bone marrow involvement. The low risk (LR) patients included six with bone/skin LCH, one with multiple bone, one with skin/bone/pituitary, one with skin/bone/brain, and one with skin only disease involvement. Fifteen patients remained on treatment from 3 weeks to over 1 year. RESULTS: Among the LR patients there were four complete responses, three partial responses, and two with no response to thalidomide. No HR patient responded to thalidomide and all died of pulmonary, liver, or bone marrow failure. Thalidomide may have played a role in the pulmonary failure. Other toxicities that required stopping therapy included neutropenia, peripheral neuropathy, and fatigue. CONCLUSIONS: Thalidomide is an effective therapy for some LR patients with LCH, but showed no significant responses in HR patients. Dose-limiting toxicities may reduce its efficacy in LR patients. Additional trials with improved anti-TNF therapies would appear warranted.     

High-dose chemotherapy in children with metastatic hepatoblastoma

BACKGROUND: Despite the advent of effective chemotherapy,a poor prognosis has been reported for patients with metastatic hepatoblastoma. To improve this prognosis, we conducted high-dose chemotherapy with autologous bone marrow rescue in patients with metastatic hepatoblastoma. METHODS AND RESULTS: Three patients were treated with high-dose chemotherapy. In patient 1, high-dose chemotherapy was given after the patient's first pulmonary relapse.Additional pulmonary metastases, which developed more than 6 months after high-dose chemotherapy, were treated by multiple thoracotomy without additional chemotherapy. Patient 2 presented additional pulmonary metastases soon after the end of the first thoracotomy and high-dose chemotherapy. Because of a decreased serum alpha-fetoprotein level after re-excision of the pulmonary metastases, a second round of high-dose chemotherapy was performed. In patient 3, multiple pulmonary metasteses responded to preoperative chemotherapy and disappeared according to the chest computed tomography. Intensive treatment with a high-dose chemotherapeutic regimen was performed at the end of postoperative chemotherapy. All three patients are alive and well, more than 6 years after receiving their diagnosis. CONCLUSION: The role of high-dose chemotherapy in treatment of metastatic hepatoblastoma could not be clarified,because of the small number of patients. However, the better outcome of our patients indicates that multimodal therapy, including high-dose chemotherapy, may improve the outcome of the patients with metastatic hepatoblastoma.     

The relevance of surgical therapy for bilateral and/or multiple pulmonary metastases in children.

PURPOSE: Pulmonary surgery is frequently used for the treatment of metastases in children with various malignant diseases. The benefit of an aggressive surgical treatment in children with bilateral and/or multiple pulmonary metastases is still discussed controversially. METHODS: A retrospective analysis of 10 children (7 girls, 3 boys; age range from 2 to 16.5 years) who underwent thoracotomy for bilateral and/or multiple pulmonary metastases was performed. The primary malignancies were osteosarcoma (n = 4), hepatoblastoma (n = 3), malignant peripheral nerve sheath tumor (n = 1), adrenocortical carcinoma (n = 1) and alveolar rhabdomyosarcoma (n = 1). Unilateral but multiple pulmonary metastases were found in 3 children. 7 patients showed bilateral pulmonary metastases. Preoperative induction chemotherapy with tumor regression and a subsequent decrease in the size and number of pulmonary metastases was mandatory for the surgery of metastases. RESULTS: Standardized bilateral thoracotomy was performed in 4 patients in 1 operation (in 1 patient combined with a hemihepatectomy), and in 3 patients, in 2 operations on different days. 5 children underwent re-thoracotomy due to recurrent pulmonary metastases (2 patients: unilateral; 3 patients: bilateral; 1 patient: twice bilateral). All visible and palpable metastases (1 - 25) were excised, either by wedge resection, by segment resection or by lobectomy. Postoperative artificial ventilation was necessary for 0 to 24 hours. Postoperative complications included intrathoracic secondary hemorrhage in 3 cases and pneumonia in 1 patient. 2 patients (20%) died of recurrent metastatic disease (osteosarcoma: 1; adrenocortical carcinoma: 1). During a mean follow-up period of 49 months (14 to 66 months after the last thoracotomy), 8 patients (80%) remained in complete remission without clinically relevant respiratory restrictions. CONCLUSION: Complete surgical resection of pulmonary metastases after response to induction chemotherapy may increase survival in carefully selected children, even in cases with multiple and recurrent metastatic disease. In children, bilateral thoracotomy within a single operation is possible without an increased complication rate.     

Concordant rhabdoid tumor of the kidney in a set of identical twins with discordant outcomes

We report identical twin boys who each had stage IV rhabdoid tumor of the left kidney at the age of 5 months and 2 years, respectively. The 5-month-old boy, despite receiving chemotherapy, died of progressive disease at the age of 12 months. Following resection of the tumor, his twin brother was treated with 6 cycles of combination chemotherapy consisting of cisplatinum, doxorubicin, vincristine, cyclophosphamide, and actinomycin-D alternating with ifosfamide and etoposide. After complete regression of lung and brain metastases, he received high-dose thiotepa, etoposide, and cyclophosphamide, followed by autologous peripheral stem cell rescue. The patient is presently alive and free of disease 6 years posttransplant. High-dose chemotherapy followed by autologous stem cell transplant may be an effective front-line therapeutic approach for patients with metastatic rhabdoid tumor of the kidney.     

Experience with aggressive therapy in three children with unresectable malignant liver tumors

BACKGROUND: Children with malignant liver tumors often present with unresectable disease but need not be considered incurable. The advent of effective chemotherapy makes aggressive management feasible, as our experience with three such patients demonstrates. Procedure and Results One child with an unresectable undifferentiated sarcoma of the liver and two others with unresectable primary hepatoblastoma and lung metastases were treated with initial chemotherapy, followed by aggressive surgical management. Treatment with chemotherapy followed by hepatectomy and liver transplantation (cadaveric or live donor) in two children has resulted in disease-free survivals of 79 and 38 months. The third patient is alive and well 24 months following chemotherapy and aggressive resection of the primary and 12 metastatic lesions. CONCLUSIONS: Initial chemotherapy for unresectable liver tumors with or without metastases is supported by the review of the literature. Consideration of orthotopic liver transplantation (OLT) from cadaveric or living related donor is warranted when the malignancy is demonstrably chemosensitive, independent of initial staging. Aggressive resection of primary and metastatic disease may be called for in selected cases.     

Incidence of cirrhosis in children with chronic hepatitis

To determine the incidence of liver cirrhosis in children with chronic hepatitis, we investigated 92 children (64 were girls; mean age was 8 years 2 months) with chronic hepatitis for the presence of cirrhosis by the combined use of laparoscopy and needle liver biopsy, between 1975 and 1985. Forty-six children had hepatitis B virus-related chronic hepatitis; cirrhosis was present in 13 (32%). Cirrhosis was diagnosed by laparoscopy in 14 children and by needle liver biopsy in eight. In six patients, cirrhosis was diagnosed within the first 12 months after the clinical onset of liver disease. Forty-six children had autoimmune hepatitis; cirrhosis was present in 41 (89%). Cirrhosis was diagnosed by laparoscopy in all 41 children and by needle liver biopsy in 23 children. Cirrhosis was already present in all 10 children studied 2 to 5 months after the first sign of liver disease. Our results indicate that the incidence of cirrhosis is high in children with chronic hepatitis, especially of the autoimmune type, and that cirrhosis may occur early, irrespective of cause. A combination of laparoscopy and biopsy is more reliable than biopsy alone for the diagnosis of cirrhosis in children with chronic hepatitis.     

Long‐term outcomes of liver transplantation for hepatoblastoma: A single‐center 14‐year experience

HB is the most common primary liver tumor in children. Complete tumor excision, either by partial resection or by total hepatectomy and liver transplantation, in combination with chemotherapy provides the best chance for cure. We performed a retrospective analysis of patients who underwent liver transplantation for HB and herein present our 14‐year single‐institution experience. Twenty‐five patients underwent liver transplantation for HB at a median age of 26 months (IQR: 15‐44). Graft survival was 96%, 87%, and 80% at 1, 3, and 5 years, respectively. There were four patient deaths, three of them due to disease recurrence within the first year post‐transplant. Ten‐year overall survival was 84%. Three recipients initially presented with pulmonary metastases and underwent resection of metastatic disease, of which two are alive at 3.9 years. Of three patients who underwent salvage transplants, two are alive at 1.5 years after transplant. Non‐survivors were associated with lower median alpha fetoprotein value at presentation compared to survivors (21 707 vs 343 214; P = .04). In conclusion, the overall long‐term outcome of primary liver transplantation for HB is excellent. Tumor recurrence was the highest contributor to mortality. Even patients with completely treated pulmonary metastases prior to transplant demonstrated a favorable survival.     

Malignant melanoma in the child--2 case reports

Case histories of two infants with malignant melanoma are presented. Both tumors had developed from a congenital mole to advanced disease with lymph node metastasis at time of diagnosis, findings which are commonly correlated with poor outcome. Initially, both patients were surgically treated. From the experience with few described cases of melanoma in childhood and with a large number of adult patients, neither chemotherapy and conventional BCG immunotherapy nor irradiation seem to be an effective treatment and are accompanied by many adverse side effects. Therefore in one patient therapy was limited to surgery alone. In the other child it was followed by treatment with high-dose recombinant alpha-2-interferon (1 Mill. i.u./Kg X d) plus an H2-receptor antagonist. Unexpectedly this girl developed neurological side effects, characterized by spastic paraparesis, indicating damage to the first motoneuron. All symptoms completely resolved after discontinuation of drugs within three months. Both children have been in complete remission for 18+ and 32+ months, respectively.     

Lamivudine and high-dose interferon alpha 2a combination treatment in naïve HBeAg-positive immunoactive chronic hepatitis B in children: an East Mediterranean center’s experience

Chronic hepatitis B virus infection is among the most common causes of chronic liver disease in children. The aim of this study was to document prospectively our experiences related to lamivudine and high-dose interferon-α2a combination in naïve, e antigen positive, chronic hepatitis B virus infection treatment in children. Thirty-three children diagnosed as naïve, immunoactive chronic hepatitis B were treated with lamivudine (3 mg/kg/day) and interferon-α2a (10 MU/m², thrice weekly). Initially, lamivudine was initiated three months before interferon-α for induction, and after June 2002, both drugs were started simultaneously. After interferon-α was stopped, lamivudine alone was continued for six months. HBeAg seroconversion with the normalization of serum ALT was achieved at the end of treatment and at the end of follow-up for 20/33 patients. Initial mean alanine aminotransferase, 142.9 IU/L, decreased to a mean value of 31.4. End-treatment response and sustained response rates were 66.7% (14/21) and 50% (6/12), respectively, in patients that underwent lamivudine induction before interferon-α and in patients that began to receive the two drugs simultaneously (p=0.4). Flu-like syndrome and anorexia were the most common complaints. As our conclusions, we propose that interferon-α2a plus lamivudine combination therapy is highly successful and safe in children suffering from chronic hepatitis B. Lamivudine induction before interferon does not seem to be necessary.     

Successful chemotherapy for childhood metastatic embryonal cell carcinoma of the testicle: a preliminary report

A child with widespread metastases successfully treated with chemotherapy alone is described. One course of combination chemotherapy using cis-platinum, vinblastine, and bleomycin produced disappearance of multiple pulmonary metastatic lesions. Four courses of therapy produced shrinkage and tumor sterilization of an abdominal mass. Twenty-six months after initiation of chemotherapy the patient is well, off of all therapy for fourteen months, and free of disease or drug related complication with normal creatinine clearance and alphafetoprotein determinations. The published adult experience demonstrates that this therapy is extremely effective for the treatment of metastatic embryonal cell carcinoma of the testis in young adults, and our case report extends this favorable experience into childhood. Toxicity is substantial, but justifiable considering the poor outlook associated with widespread metastatic disease. Collectively, the reviewed data suggest that further trials of this type of therapy are indicated in children.     

Propylthiouracil-associated liver failure presenting as probable autoimmune hepatitis in a child with Graves' disease

This case describes a young girl with Graves' disease, who presented with fulminant hepatic failure 9 months into propylthiouracil (PTU) therapy. Her clinical presentation was consistent with 'probable autoimmune hepatitis,' as defined by the International Autoimmune Hepatitis Group scoring system. Despite discontinuation of PTU and high-dose steroid therapy, she required liver transplantation. Subsequent pathology could not definitively rule out autoimmune hepatitis. PTU is an important cause of drug-related liver failure in children, and clinicians should be mindful that it is frequently used in patients who already have an underlying risk of autoimmune liver disease.     

Pediatric melanoma: are recent advances in the management of adult melanoma relevant to the pediatric population

PURPOSE: Although melanoma in childhood is a rare condition, there is evidence that it is increasing in frequency. As advances are being made in the understanding and therapy of adult melanoma, we need to consider the relevance of these advances to the pediatric population. PATIENTS AND METHODS: We have reviewed our experience at the University of Colorado Health Sciences Center with the clinical parameters, therapy, and outcomes of melanoma in 27 patients age 16 years or younger and contrasted these to the adult experience. RESULTS: Most cases were diagnosed early with the median thickness of the primary melanoma being 0.75 mm. Six of seven patients who had lymph node metastases develop remain alive at a median follow-up of 62 months. Durable complete responses to a variety of therapies were seen in three of five patients with advanced disease outside the central nervous system. Our experience with sentinel node biopsy, adjuvant interferon, and new therapies for metastatic melanoma were also reviewed and appear to be relevant for younger patients. CONCLUSIONS: The behavior of melanoma in the pediatric population at our center is similar to that seen in adults. The integration of recent advances in the staging and therapy of melanoma in adults would be of benefit to children with this condition.     

Rhabdoid tumor of the kidney: complete remission induced by cis-platinum and adriamycin

A 4-month-old male infant with Stage I rhabdoid tumor of the kidney at presentation subsequently developed pulmonary metastatic disease shortly after diagnosis and initiation of Vincristine and Actinomycin D chemotherapy. The patient was then treated with cis-platinum and Adriamycin. Within 28 days he achieved a complete remission which was maintained for 5 months. Subsequent recurrent pulmonary lesions failed to regress with radiotherapy and high-dose cyclophosphamide when used as single sequential agents. Further clinical trials with cis-platinum and Adriamycin seem warranted since prognosis with this tumor is poor and successful chemotherapy after metastatic dissemination has not been previously reported.     

Isolated liver transplantation in children with cystic fibrosis – An Australian experience

Nightingale S, O’Loughlin EV, Dorney SFA, Shun A, Verran DJ, Strasser SI, McCaughan GW, Jermyn V, Van Asperen P, Gaskin KJ, Stormon MO. Isolated liver transplantation in children with cystic fibrosis – An Australian experience.
Pediatr Transplantation 2010: 14:779–785. © 2010 John Wiley & Sons A/S. Abstract: CF liver disease is an uncommon indication for pediatric LT. Determining optimal timing and type (isolated liver versus multi‐organ) of transplantation for those with severe liver disease can be challenging and involves consideration of the extent of liver disease (PHT, synthetic dysfunction) and extrahepatic factors such as pulmonary function. We present the experience of isolated LT for CF at our center. Eight children received one allograft each (3.9% of all grafts). One‐ and four‐yr survivals are both 75%. The two deaths occurred within the first two months after LT, and in both cases, invasive fungal infections were implicated, one following treatment for acute severe rejection. All had significant PHT, and six had synthetic dysfunction. All had roux‐en Y biliary anastomoses and none developed long‐term biliary complications. Seven had pulmonary colonization with Pseudomonas aeruginosa and six with fungus at time of transplantation. Mean pre‐LT FEV1 was 80% (range 59–116%) predicted, and lung function post‐LT was stable. Isolated LT in children with CF is successful in those with relatively preserved pulmonary function, which does not appear to deteriorate as a consequence. Roux‐en Y biliary anastomosis and antifungal prophylaxis should be a part of management of these patients.     

Hepatopathy following irradiation and chemotherapy for Wilms' tumor

Two children being treated with combination chemotherapy and irradiation for localized, rightsided Wilms' tumor developed sudden enlargement of the liver with defects on liver scintigram resembling liver metastases. One child also developed pancytopenia. When chemotherapy was temporarily withheld in both children, hepatomegaly and scintigram abnormalities resolved. The planned courses of chemotherapy were subsequently completed without complications. The clinical course in our patients is compared to previously published experiences. Awareness of this complication could prevent the mistaken diagnosis of metastatic disease and emphasizes the care necessary when administering cytotoxic drugs to children receiving irradiation to all or a portion of the liver.     

CCNU, vinblastine, and delalutin therapy in renal cell carcinoma.

Advanced renal cell carcinoma is relatively resistant to most adequately evaluated chemotherapeutic agents. The combination of CCNU and vinblastine, which has antitumor activity in a frog renal carcinoma model system, has demonstrated activity in initial studies in man. The current study investigated this combination of drugs together with a progestational agent, Delalutin. Seventeen patients with metastatic renal cell carcinoma were treated with CCNU, vinblastine and Delalutin. There were no objective responses. Four patients with stable disease had a mean survival of 18 months compared to 13 patients with progressive disease who had a mean survival of 5 months. The survival of the four patients with stable disease was in large part due to the slowly progressive natural history of their disease.