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Milton J Finegold - One of the best experts on this subject based on the ideXlab platform.
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minimal adjuvant chemotherapy for children with Hepatoblastoma resected at diagnosis ahep0731 a children s oncology group multicentre phase 3 trial
Lancet Oncology, 2019Co-Authors: Howard M Katzenstein, Milton J Finegold, Marcio H Malogolowkin, Mark Krailo, Alexander J Towbin, Max R Langham, Mary Beth Mccarville, Sarangarajan RanganathanAbstract:Summary Background Hepatoblastoma treatment with curative intent requires surgical resection, but only about a third of newly diagnosed patients with Hepatoblastoma have resectable disease at diagnosis. Patients who have upfront resection typically receive a total of 4–6 cycles of adjuvant chemotherapy post-surgery, with the combination of cisplatin, fluorouracil, and vincristine. We aimed to investigate whether event-free survival in children with Hepatoblastoma who had complete resection at diagnosis could be maintained with two cycles of adjuvant chemotherapy. Methods In this Children's Oncology Group, multicentre, phase 3 trial, patients were enrolled in four risk groups on the basis of Evans surgical stage, tumour histology, and levels of α-fetoprotein at diagnosis to receive risk-adapted therapy. Here, we report on the low-risk stratum of the trial. Eligible patients were younger than 21 years and had histologically confirmed, stage I or II Hepatoblastoma without 100% pure fetal stage I or small-cell undifferentiated histology; elevated serum α-fetoprotein level (>100 ng/mL); a complete resection at diagnosis; at least 50% Karnofsky (patients >16 years) or Lansky (patients ≤16 years) performance status; and had received no previous chemotherapy or other Hepatoblastoma-directed therapy. Patients received two 21-day cycles of cisplatin, fluorouracil, and vincristine within 42 days of resection, consisting of cisplatin (100 mg/m2 per dose or 3·3 mg/kg per dose for children ClinicalTrials.gov , number NCT00980460 , and is now permanently closed to accrual. Findings Between May 18, 2010, and May 28, 2014, 51 patients in 32 centres in two countries were enrolled into the low-risk stratum of this trial, of whom 49 received c hemotherapy treatment after surgery and were evaluable for activity and safety. Median follow-up time for all evaluable patients was 42 months (IQR 36–62). 4-year event-free survival was 92% (95% CI 79–97) and 5-year event-free survival was 88% (72–95). Two (4%) of 49 patients had surgical complications (bile leaks). The most common grade 3–4 adverse events were febrile neutropenia in seven (14%) patients, decreased neutrophil count in three (6%) patients, infections in four (8%) patients, and diarrhoea in four (8%) patients. Ototoxicity occurred in one (2%) patient. One (2%) patient of the three who relapsed in this cohort died from disease. Two (4%) patients died in clinical remission after therapy discontinuation. One patient died of pneumonia and bacterial sepsis 1 year after therapy discontinuation and another patient died of unrelated causes 57 months after therapy completion. There were no treatment-related deaths. Interpretation Minimal postoperative chemotherapy with two cycles of cisplatin, fluorouracil, and vincristine can ensure disease control in patients with Hepatoblastoma resected at diagnosis. Our results show that dose reduction of ototoxic agents is a safe, effective treatment for these children. Funding National Institutes of Health
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upfront window vincristine irinotecan treatment of high risk Hepatoblastoma a report from the children s oncology group ahep0731 study committee
Cancer, 2017Co-Authors: Howard M Katzenstein, Milton J Finegold, Sarangarajan Ranganathan, Marcio H Malogolowkin, Mark Krailo, Wayne L Furman, Beth M Mccarville, Alexander J Towbin, Greg Tiao, Stephen P DunnAbstract:BACKGROUND The identification of new therapies for high-risk (HR) Hepatoblastoma is challenging. Children's Oncology Group study AHEP0731 included a HR stratum to explore the efficacy of novel agents. Herein, the authors report the response rate to the combination of vincristine (V) and irinotecan (I) and the outcome of patients with high-risk Hepatoblastoma. METHODS Patients with newly diagnosed metastatic Hepatoblastoma or those with a serum α-fetoprotein (AFP) level 1 log10) decline in their AFP level. Responders were to receive 2 additional cycles of VI intermixed with 6 cycles of the combination of cisplatin, doxorubicin, 5-fluorouracil, and vincristine (C5VD). Nonresponders were to receive 6 cycles of C5VD alone. RESULTS A total of 32 patients with a median age at diagnosis of 26 months (range, 11-159 months) were enrolled between September 2009 and February 2012. Fourteen of 30 evaluable patients were responders (RECIST and AFP in 6 patients, RECIST only in 3 patients, and AFP only in 5 patients). The median AFP decline after 2 cycles of VI for the entire group was 345,565 ng/mL (85% of the initial AFP). The 3-year event-free and overall survival rates were 49% (95% confidence interval, 30%-65%) and 62% (95% confidence interval, 42%-77%), respectively. CONCLUSIONS The VI combination appears to have substantial activity against HR Hepatoblastoma. The ultimate impact of this regimen in improving the outcomes of children with HR Hepatoblastoma remains to be determined. Cancer 2017;123:2360–2367. © 2017 American Cancer Society.
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Hepatoblastoma arising in a pigmented β catenin activated hepatocellular adenoma case report and review of the literature
The American Journal of Surgical Pathology, 2016Co-Authors: Christine Y Louie, Milton J Finegold, Waldo Concepcion, Joseph K Park, Arun Rangaswami, Florette K HazardAbstract:Hepatoblastoma is the most common malignant liver tumor in childhood. It has been associated with a variety of constitutional syndromes and gene mutations. However, there are very few reports of associations with pediatric hepatocellular adenomas (HCAs) and no reported associations with pigmented HCAs (P-HCAs). We present a unique case of Hepatoblastoma arising in a background of 2 β-catenin-activated HCAs, one of which is pigmented, in a 4-year-old child. The gross, histologic, and immunohistochemical features are described for each tumor. In addition, the literature is reviewed with specific emphasis on the clinical and pathologic features of B-HCAs. Although the potential of β-catenin-activated HCAs to progress to hepatocellular carcinoma has been well documented, there are very few reports of their potential to progress to Hepatoblastoma. We not only present such a case, but, to our knowledge, we also present the first case of a P-HCA in a child.
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vincristine irinotecan upfront window treatment of high risk Hepatoblastoma a report from the children s oncology group cog ahep0731 study committee
Journal of Clinical Oncology, 2016Co-Authors: Howard M Katzenstein, Milton J Finegold, Sarangarajan Ranganathan, Marcio H Malogolowkin, Mark Krailo, Wayne L Furman, Alexander J Towbin, Greg Tiao, Mary Beth Mccarville, Stephen P DunnAbstract:10516Background: The identification of new therapies for high-risk (HR) Hepatoblastoma (HB) is challenging. Children’s Oncology Group Study AHEP0731 included a HR stratum to explore novel agents. W...
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complete surgical resection is curative for children with Hepatoblastoma with pure fetal histology a report from the children s oncology group
Journal of Clinical Oncology, 2011Co-Authors: Marcio H Malogolowkin, Rebecka L Meyers, Howard M Katzenstein, Mark Krailo, Jon M Rowland, Joel E Haas, Milton J FinegoldAbstract:Purpose Children with pure fetal histology (PFH) Hepatoblastoma treated with complete surgical resection and minimal adjuvant therapy have been shown to have excellent outcomes when compared with other patients with Hepatoblastoma. We prospectively studied the safety and efficacy of reducing therapy in all children with stage I PFH enrolled onto two consecutive studies. Patients and Methods From August 1989 to December 1992, 9 children with stage I PFH were treated on the Intergroup Hepatoblastoma study INT-0098 and were nonrandomly assigned to receive chemotherapy after surgical resection with single-agent bolus doxorubicin for 3 consecutive days. From March 1999 to November 2006, 16 children with stage I PFH enrolled onto Children's Oncology Group Study P9645 were treated with observation after resection. Central confirmation of the histologic diagnosis by a study group pathologist was mandated. The extent of liver disease was assigned retrospectively according to the pretreatment extent of disease (PRE...
Marcio H Malogolowkin - One of the best experts on this subject based on the ideXlab platform.
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minimal adjuvant chemotherapy for children with Hepatoblastoma resected at diagnosis ahep0731 a children s oncology group multicentre phase 3 trial
Lancet Oncology, 2019Co-Authors: Howard M Katzenstein, Milton J Finegold, Marcio H Malogolowkin, Mark Krailo, Alexander J Towbin, Max R Langham, Mary Beth Mccarville, Sarangarajan RanganathanAbstract:Summary Background Hepatoblastoma treatment with curative intent requires surgical resection, but only about a third of newly diagnosed patients with Hepatoblastoma have resectable disease at diagnosis. Patients who have upfront resection typically receive a total of 4–6 cycles of adjuvant chemotherapy post-surgery, with the combination of cisplatin, fluorouracil, and vincristine. We aimed to investigate whether event-free survival in children with Hepatoblastoma who had complete resection at diagnosis could be maintained with two cycles of adjuvant chemotherapy. Methods In this Children's Oncology Group, multicentre, phase 3 trial, patients were enrolled in four risk groups on the basis of Evans surgical stage, tumour histology, and levels of α-fetoprotein at diagnosis to receive risk-adapted therapy. Here, we report on the low-risk stratum of the trial. Eligible patients were younger than 21 years and had histologically confirmed, stage I or II Hepatoblastoma without 100% pure fetal stage I or small-cell undifferentiated histology; elevated serum α-fetoprotein level (>100 ng/mL); a complete resection at diagnosis; at least 50% Karnofsky (patients >16 years) or Lansky (patients ≤16 years) performance status; and had received no previous chemotherapy or other Hepatoblastoma-directed therapy. Patients received two 21-day cycles of cisplatin, fluorouracil, and vincristine within 42 days of resection, consisting of cisplatin (100 mg/m2 per dose or 3·3 mg/kg per dose for children ClinicalTrials.gov , number NCT00980460 , and is now permanently closed to accrual. Findings Between May 18, 2010, and May 28, 2014, 51 patients in 32 centres in two countries were enrolled into the low-risk stratum of this trial, of whom 49 received c hemotherapy treatment after surgery and were evaluable for activity and safety. Median follow-up time for all evaluable patients was 42 months (IQR 36–62). 4-year event-free survival was 92% (95% CI 79–97) and 5-year event-free survival was 88% (72–95). Two (4%) of 49 patients had surgical complications (bile leaks). The most common grade 3–4 adverse events were febrile neutropenia in seven (14%) patients, decreased neutrophil count in three (6%) patients, infections in four (8%) patients, and diarrhoea in four (8%) patients. Ototoxicity occurred in one (2%) patient. One (2%) patient of the three who relapsed in this cohort died from disease. Two (4%) patients died in clinical remission after therapy discontinuation. One patient died of pneumonia and bacterial sepsis 1 year after therapy discontinuation and another patient died of unrelated causes 57 months after therapy completion. There were no treatment-related deaths. Interpretation Minimal postoperative chemotherapy with two cycles of cisplatin, fluorouracil, and vincristine can ensure disease control in patients with Hepatoblastoma resected at diagnosis. Our results show that dose reduction of ototoxic agents is a safe, effective treatment for these children. Funding National Institutes of Health
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upfront window vincristine irinotecan treatment of high risk Hepatoblastoma a report from the children s oncology group ahep0731 study committee
Cancer, 2017Co-Authors: Howard M Katzenstein, Milton J Finegold, Sarangarajan Ranganathan, Marcio H Malogolowkin, Mark Krailo, Wayne L Furman, Beth M Mccarville, Alexander J Towbin, Greg Tiao, Stephen P DunnAbstract:BACKGROUND The identification of new therapies for high-risk (HR) Hepatoblastoma is challenging. Children's Oncology Group study AHEP0731 included a HR stratum to explore the efficacy of novel agents. Herein, the authors report the response rate to the combination of vincristine (V) and irinotecan (I) and the outcome of patients with high-risk Hepatoblastoma. METHODS Patients with newly diagnosed metastatic Hepatoblastoma or those with a serum α-fetoprotein (AFP) level 1 log10) decline in their AFP level. Responders were to receive 2 additional cycles of VI intermixed with 6 cycles of the combination of cisplatin, doxorubicin, 5-fluorouracil, and vincristine (C5VD). Nonresponders were to receive 6 cycles of C5VD alone. RESULTS A total of 32 patients with a median age at diagnosis of 26 months (range, 11-159 months) were enrolled between September 2009 and February 2012. Fourteen of 30 evaluable patients were responders (RECIST and AFP in 6 patients, RECIST only in 3 patients, and AFP only in 5 patients). The median AFP decline after 2 cycles of VI for the entire group was 345,565 ng/mL (85% of the initial AFP). The 3-year event-free and overall survival rates were 49% (95% confidence interval, 30%-65%) and 62% (95% confidence interval, 42%-77%), respectively. CONCLUSIONS The VI combination appears to have substantial activity against HR Hepatoblastoma. The ultimate impact of this regimen in improving the outcomes of children with HR Hepatoblastoma remains to be determined. Cancer 2017;123:2360–2367. © 2017 American Cancer Society.
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vincristine irinotecan upfront window treatment of high risk Hepatoblastoma a report from the children s oncology group cog ahep0731 study committee
Journal of Clinical Oncology, 2016Co-Authors: Howard M Katzenstein, Milton J Finegold, Sarangarajan Ranganathan, Marcio H Malogolowkin, Mark Krailo, Wayne L Furman, Alexander J Towbin, Greg Tiao, Mary Beth Mccarville, Stephen P DunnAbstract:10516Background: The identification of new therapies for high-risk (HR) Hepatoblastoma (HB) is challenging. Children’s Oncology Group Study AHEP0731 included a HR stratum to explore novel agents. W...
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effect of neoadjuvant chemotherapy on resectability of stage iii and iv Hepatoblastoma
British Journal of Surgery, 2014Co-Authors: Rajkumar Venkatramani, James E Stein, A Sapra, Yuri Genyk, V Jhaveri, Marcio H Malogolowkin, Leo MascarenhasAbstract:Background The potential for surgical resection of primary Hepatoblastoma tumours was assessed at diagnosis, and after two and four cycles of neoadjuvant chemotherapy. Methods Available radiographic images for patients with stage III and IV Hepatoblastoma diagnosed between 1991 and 2008 were reviewed. The extent of disease was determined at diagnosis using the PRETEXT staging system, and after two and four cycles of therapy by POST-TEXT staging. Tumour resectability based on radiographic studies was assessed independently by two surgeons with expertise in hepatic surgery who were blinded to treatment and clinical outcome. Results Radiographic images from 20 patients with Hepatoblastoma were reviewed. Six of 20 tumours were downstaged after two cycles, and three additional tumours were downstaged following four cycles. All PRETEXT stage III and IV tumours were determined to be surgically unresectable at diagnosis. The number of tumours considered unresectable decreased from 16 of 20 at diagnosis to seven of 20 after two cycles, and to four of 20 after four cycles. Five of the seven tumours that were unresectable after two cycles, and all four tumours that were unresectable after four cycles would have qualified for liver transplant based on radiographic studies. Conclusion The majority of stage III and IV Hepatoblastomas achieved radiographic resectability after two cycles of chemotherapy. There may be an opportunity for earlier surgical intervention and potential for a reduction in chemotherapy in a considerable number of patients.
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Hepatoblastoma state of the art pathology genetics risk stratification and chemotherapy
Current Opinion in Pediatrics, 2014Co-Authors: Piotr Czauderna, Dolores Lopezterrada, Marcio H Malogolowkin, Beate Haberle, Eiso Hiyama, Rebecka L MeyersAbstract:Purpose of reviewAs a rare pediatric tumor, Hepatoblastoma presents challenges to the individual practitioner as no center will see more than a handful of cases each year.Recent findingsThe Children's Hepatic tumor International Collaborative (CHIC) effort has fostered international cooperation in t
Sarangarajan Ranganathan - One of the best experts on this subject based on the ideXlab platform.
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minimal adjuvant chemotherapy for children with Hepatoblastoma resected at diagnosis ahep0731 a children s oncology group multicentre phase 3 trial
Lancet Oncology, 2019Co-Authors: Howard M Katzenstein, Milton J Finegold, Marcio H Malogolowkin, Mark Krailo, Alexander J Towbin, Max R Langham, Mary Beth Mccarville, Sarangarajan RanganathanAbstract:Summary Background Hepatoblastoma treatment with curative intent requires surgical resection, but only about a third of newly diagnosed patients with Hepatoblastoma have resectable disease at diagnosis. Patients who have upfront resection typically receive a total of 4–6 cycles of adjuvant chemotherapy post-surgery, with the combination of cisplatin, fluorouracil, and vincristine. We aimed to investigate whether event-free survival in children with Hepatoblastoma who had complete resection at diagnosis could be maintained with two cycles of adjuvant chemotherapy. Methods In this Children's Oncology Group, multicentre, phase 3 trial, patients were enrolled in four risk groups on the basis of Evans surgical stage, tumour histology, and levels of α-fetoprotein at diagnosis to receive risk-adapted therapy. Here, we report on the low-risk stratum of the trial. Eligible patients were younger than 21 years and had histologically confirmed, stage I or II Hepatoblastoma without 100% pure fetal stage I or small-cell undifferentiated histology; elevated serum α-fetoprotein level (>100 ng/mL); a complete resection at diagnosis; at least 50% Karnofsky (patients >16 years) or Lansky (patients ≤16 years) performance status; and had received no previous chemotherapy or other Hepatoblastoma-directed therapy. Patients received two 21-day cycles of cisplatin, fluorouracil, and vincristine within 42 days of resection, consisting of cisplatin (100 mg/m2 per dose or 3·3 mg/kg per dose for children ClinicalTrials.gov , number NCT00980460 , and is now permanently closed to accrual. Findings Between May 18, 2010, and May 28, 2014, 51 patients in 32 centres in two countries were enrolled into the low-risk stratum of this trial, of whom 49 received c hemotherapy treatment after surgery and were evaluable for activity and safety. Median follow-up time for all evaluable patients was 42 months (IQR 36–62). 4-year event-free survival was 92% (95% CI 79–97) and 5-year event-free survival was 88% (72–95). Two (4%) of 49 patients had surgical complications (bile leaks). The most common grade 3–4 adverse events were febrile neutropenia in seven (14%) patients, decreased neutrophil count in three (6%) patients, infections in four (8%) patients, and diarrhoea in four (8%) patients. Ototoxicity occurred in one (2%) patient. One (2%) patient of the three who relapsed in this cohort died from disease. Two (4%) patients died in clinical remission after therapy discontinuation. One patient died of pneumonia and bacterial sepsis 1 year after therapy discontinuation and another patient died of unrelated causes 57 months after therapy completion. There were no treatment-related deaths. Interpretation Minimal postoperative chemotherapy with two cycles of cisplatin, fluorouracil, and vincristine can ensure disease control in patients with Hepatoblastoma resected at diagnosis. Our results show that dose reduction of ototoxic agents is a safe, effective treatment for these children. Funding National Institutes of Health
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upfront window vincristine irinotecan treatment of high risk Hepatoblastoma a report from the children s oncology group ahep0731 study committee
Cancer, 2017Co-Authors: Howard M Katzenstein, Milton J Finegold, Sarangarajan Ranganathan, Marcio H Malogolowkin, Mark Krailo, Wayne L Furman, Beth M Mccarville, Alexander J Towbin, Greg Tiao, Stephen P DunnAbstract:BACKGROUND The identification of new therapies for high-risk (HR) Hepatoblastoma is challenging. Children's Oncology Group study AHEP0731 included a HR stratum to explore the efficacy of novel agents. Herein, the authors report the response rate to the combination of vincristine (V) and irinotecan (I) and the outcome of patients with high-risk Hepatoblastoma. METHODS Patients with newly diagnosed metastatic Hepatoblastoma or those with a serum α-fetoprotein (AFP) level 1 log10) decline in their AFP level. Responders were to receive 2 additional cycles of VI intermixed with 6 cycles of the combination of cisplatin, doxorubicin, 5-fluorouracil, and vincristine (C5VD). Nonresponders were to receive 6 cycles of C5VD alone. RESULTS A total of 32 patients with a median age at diagnosis of 26 months (range, 11-159 months) were enrolled between September 2009 and February 2012. Fourteen of 30 evaluable patients were responders (RECIST and AFP in 6 patients, RECIST only in 3 patients, and AFP only in 5 patients). The median AFP decline after 2 cycles of VI for the entire group was 345,565 ng/mL (85% of the initial AFP). The 3-year event-free and overall survival rates were 49% (95% confidence interval, 30%-65%) and 62% (95% confidence interval, 42%-77%), respectively. CONCLUSIONS The VI combination appears to have substantial activity against HR Hepatoblastoma. The ultimate impact of this regimen in improving the outcomes of children with HR Hepatoblastoma remains to be determined. Cancer 2017;123:2360–2367. © 2017 American Cancer Society.
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novel advances in understanding of molecular pathogenesis of Hepatoblastoma a wnt β catenin perspective
Gene Expression, 2017Co-Authors: Danielle Bell, Sarangarajan Ranganathan, Junyan Tao, Satdarshan P S MongaAbstract:Hepatoblastoma is the most common pediatric liver malignancy, typically striking children within the first 3 years of their young lives. While advances in chemotherapy and newer surgical techniques have improved survival in patients with localized disease, unfortunately, for the 25% of patients with metastasis, the overall survival remains poor. These tumors, which are thought to arise from hepatic progenitors or hepatoblasts, hence the name Hepatoblastoma, can be categorized by histological subtyping based on their level of cell differentiation. Genomic and histological analysis of human tumor samples has shown exon-3 deletions or missense mutations in gene coding for β-catenin, a downstream effector of the Wnt signaling pathway, in up to 90% of Hepatoblastoma cases. The current article will review key aberrations in molecular pathways that are implicated in various subtypes of Hepatoblastoma with an emphasis on Wnt signaling. It will also discuss cooperation among components of pathways such as β-catenin and Yes-associated protein in cancer development. Understanding the complex network of molecular signaling in oncogenesis will undoubtedly aid in the discovery of new therapeutics to help combat Hepatoblastoma.
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vincristine irinotecan upfront window treatment of high risk Hepatoblastoma a report from the children s oncology group cog ahep0731 study committee
Journal of Clinical Oncology, 2016Co-Authors: Howard M Katzenstein, Milton J Finegold, Sarangarajan Ranganathan, Marcio H Malogolowkin, Mark Krailo, Wayne L Furman, Alexander J Towbin, Greg Tiao, Mary Beth Mccarville, Stephen P DunnAbstract:10516Background: The identification of new therapies for high-risk (HR) Hepatoblastoma (HB) is challenging. Children’s Oncology Group Study AHEP0731 included a HR stratum to explore novel agents. W...
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activation of β catenin and yap1 in human Hepatoblastoma and induction of hepatocarcinogenesis in mice
Gastroenterology, 2014Co-Authors: Junyan Tao, Sarangarajan Ranganathan, Diego F Calvisi, Antonio Cigliano, Lili Zhou, Sucha Singh, Lijie Jiang, Biao Fan, Luigi TerraccianoAbstract:Background & Aims Aberrant activation of β-catenin and Yes-associated protein 1 (Yap1) signaling pathways have been associated with the development of multiple tumor types. Yap functions as a transcriptional coactivator by interacting with TEA domain DNA binding proteins. We investigated the interactions among these pathways during hepatic tumorigenesis. Methods We used immunohistochemical analysis to determine expression of β-catenin and Yap1 in liver cancer specimens collected from patients in Europe and the United States, consisting of 104 hepatocellular carcinoma, 62 intrahepatic cholangiocarcinoma, and 94 Hepatoblastoma samples. We assessed β-catenin and Yap1 signaling and interactions in Hepatoblastoma cell lines ((HuH6, HepG2, HepT1, HC-AFW1, HepG2, and HC-AFW1); proteins were knocked down with small interfering RNAs, and effects on proliferation and cell death were measured. Sleeping beauty–mediated hydrodynamic transfection was used to overexpress constitutively active forms of β-catenin (ΔN90/β-catenin) and Yap1 (YapS127A) in livers of mice; tissues were collected, and histological and immunohistochemical analyses were performed. Results We observed nuclear localization of β-catenin and Yap1 in 79% of Hepatoblastoma samples but not in most hepatocellular carcinoma or intrahepatic cholangiocarcinoma samples. Yap1 and β-catenin coprecipitated in Hepatoblastoma but not hepatocellular carcinoma cells. Small interfering RNA–mediated knockdown of Yap1 or β-catenin in Hepatoblastoma cells reduced proliferation in an additive manner. Knockdown of Yap1 reduced its ability to coactivate transcription with β-catenin; β-catenin inhibitors inactivated Yap1. Overexpression of constitutively active forms of Yap1 and β-catenin in mouse liver led to rapid tumorigenesis, with 100% mortality by 11 weeks. Tumor cells expressed both proteins, and human Hepatoblastoma cells expressed common targets of their 2 signaling pathways. Yap1 binding of TEA domain factors was required for tumorigenesis in mice. Conclusions β-catenin and the transcriptional regulator Yap1 interact physically and are activated in most human Hepatoblastoma tissues; overexpression of activated forms of these proteins in livers of mice leads to rapid tumor development. Further analysis of these mice will allow further studies of these pathways in Hepatoblastoma pathogenesis and could lead to the identification of new therapeutic targets.
Howard M Katzenstein - One of the best experts on this subject based on the ideXlab platform.
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minimal adjuvant chemotherapy for children with Hepatoblastoma resected at diagnosis ahep0731 a children s oncology group multicentre phase 3 trial
Lancet Oncology, 2019Co-Authors: Howard M Katzenstein, Milton J Finegold, Marcio H Malogolowkin, Mark Krailo, Alexander J Towbin, Max R Langham, Mary Beth Mccarville, Sarangarajan RanganathanAbstract:Summary Background Hepatoblastoma treatment with curative intent requires surgical resection, but only about a third of newly diagnosed patients with Hepatoblastoma have resectable disease at diagnosis. Patients who have upfront resection typically receive a total of 4–6 cycles of adjuvant chemotherapy post-surgery, with the combination of cisplatin, fluorouracil, and vincristine. We aimed to investigate whether event-free survival in children with Hepatoblastoma who had complete resection at diagnosis could be maintained with two cycles of adjuvant chemotherapy. Methods In this Children's Oncology Group, multicentre, phase 3 trial, patients were enrolled in four risk groups on the basis of Evans surgical stage, tumour histology, and levels of α-fetoprotein at diagnosis to receive risk-adapted therapy. Here, we report on the low-risk stratum of the trial. Eligible patients were younger than 21 years and had histologically confirmed, stage I or II Hepatoblastoma without 100% pure fetal stage I or small-cell undifferentiated histology; elevated serum α-fetoprotein level (>100 ng/mL); a complete resection at diagnosis; at least 50% Karnofsky (patients >16 years) or Lansky (patients ≤16 years) performance status; and had received no previous chemotherapy or other Hepatoblastoma-directed therapy. Patients received two 21-day cycles of cisplatin, fluorouracil, and vincristine within 42 days of resection, consisting of cisplatin (100 mg/m2 per dose or 3·3 mg/kg per dose for children ClinicalTrials.gov , number NCT00980460 , and is now permanently closed to accrual. Findings Between May 18, 2010, and May 28, 2014, 51 patients in 32 centres in two countries were enrolled into the low-risk stratum of this trial, of whom 49 received c hemotherapy treatment after surgery and were evaluable for activity and safety. Median follow-up time for all evaluable patients was 42 months (IQR 36–62). 4-year event-free survival was 92% (95% CI 79–97) and 5-year event-free survival was 88% (72–95). Two (4%) of 49 patients had surgical complications (bile leaks). The most common grade 3–4 adverse events were febrile neutropenia in seven (14%) patients, decreased neutrophil count in three (6%) patients, infections in four (8%) patients, and diarrhoea in four (8%) patients. Ototoxicity occurred in one (2%) patient. One (2%) patient of the three who relapsed in this cohort died from disease. Two (4%) patients died in clinical remission after therapy discontinuation. One patient died of pneumonia and bacterial sepsis 1 year after therapy discontinuation and another patient died of unrelated causes 57 months after therapy completion. There were no treatment-related deaths. Interpretation Minimal postoperative chemotherapy with two cycles of cisplatin, fluorouracil, and vincristine can ensure disease control in patients with Hepatoblastoma resected at diagnosis. Our results show that dose reduction of ototoxic agents is a safe, effective treatment for these children. Funding National Institutes of Health
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upfront window vincristine irinotecan treatment of high risk Hepatoblastoma a report from the children s oncology group ahep0731 study committee
Cancer, 2017Co-Authors: Howard M Katzenstein, Milton J Finegold, Sarangarajan Ranganathan, Marcio H Malogolowkin, Mark Krailo, Wayne L Furman, Beth M Mccarville, Alexander J Towbin, Greg Tiao, Stephen P DunnAbstract:BACKGROUND The identification of new therapies for high-risk (HR) Hepatoblastoma is challenging. Children's Oncology Group study AHEP0731 included a HR stratum to explore the efficacy of novel agents. Herein, the authors report the response rate to the combination of vincristine (V) and irinotecan (I) and the outcome of patients with high-risk Hepatoblastoma. METHODS Patients with newly diagnosed metastatic Hepatoblastoma or those with a serum α-fetoprotein (AFP) level 1 log10) decline in their AFP level. Responders were to receive 2 additional cycles of VI intermixed with 6 cycles of the combination of cisplatin, doxorubicin, 5-fluorouracil, and vincristine (C5VD). Nonresponders were to receive 6 cycles of C5VD alone. RESULTS A total of 32 patients with a median age at diagnosis of 26 months (range, 11-159 months) were enrolled between September 2009 and February 2012. Fourteen of 30 evaluable patients were responders (RECIST and AFP in 6 patients, RECIST only in 3 patients, and AFP only in 5 patients). The median AFP decline after 2 cycles of VI for the entire group was 345,565 ng/mL (85% of the initial AFP). The 3-year event-free and overall survival rates were 49% (95% confidence interval, 30%-65%) and 62% (95% confidence interval, 42%-77%), respectively. CONCLUSIONS The VI combination appears to have substantial activity against HR Hepatoblastoma. The ultimate impact of this regimen in improving the outcomes of children with HR Hepatoblastoma remains to be determined. Cancer 2017;123:2360–2367. © 2017 American Cancer Society.
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vincristine irinotecan upfront window treatment of high risk Hepatoblastoma a report from the children s oncology group cog ahep0731 study committee
Journal of Clinical Oncology, 2016Co-Authors: Howard M Katzenstein, Milton J Finegold, Sarangarajan Ranganathan, Marcio H Malogolowkin, Mark Krailo, Wayne L Furman, Alexander J Towbin, Greg Tiao, Mary Beth Mccarville, Stephen P DunnAbstract:10516Background: The identification of new therapies for high-risk (HR) Hepatoblastoma (HB) is challenging. Children’s Oncology Group Study AHEP0731 included a HR stratum to explore novel agents. W...
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outcomes for patients with congenital Hepatoblastoma
Pediatric Blood & Cancer, 2013Co-Authors: Angela D Trobaughlotrario, Gail E. Tomlinson, Dietrich Von Schweinitz, Marcio H Malogolowkin, Barbara H Chaiyachati, Rebecka L Meyers, Beate Haberle, Howard M Katzenstein, Mark Krailo, James H FeusnerAbstract:Background Congenital Hepatoblastoma, diagnosed in the first month of life, has been reported to have a poor prognosis; however, a comprehensive evaluation of this entity is lacking. Procedure We retrospectively reviewed two patients from the senior authors' personal series and 25 cases identified in the databases of several multicenter group studies (INT-0098, P9645, 881, P9346, HB 89, HB94, and HB 99). We compared this series with cases of congenital Hepatoblastoma previously published in the literature. Results The 3-year survival in our case series was 86% (18/21) with a follow-up of 44–230 months (median 85.5 months). Presentation and treatment were not substantially different from Hepatoblastoma cohorts unselected for age. Survival was comparable to the reported disease free survival for a similar cohort of Hepatoblastoma patients unselected for age between 1986 and 2002 (82.5%) [von Schweinitz et al., Eur J Cancer 1997; 33:1243–1249]. The 2-year survival of cases reported in the literature was 0% (0/9) and 42% (10/24) for patients reported before and after 1990, respectively. Conclusions Congenital Hepatoblastoma does not appear to confer a worse prognosis. The improved survival of our current series of patients, collected from the past 20 years of German and American multicenter trials and personal series, suggests that the outcome of Hepatoblastoma at this young age is much better than has been historically reported. More rigorous analysis should be conducted in future multicenter trials. It is possible that congenital Hepatoblastoma should be treated like all other patients with Hepatoblastoma provided that the child is stable enough to proceed with surgery and chemotherapy. Pediatr Blood Cancer 2013;60:1817–1825. © 2013 Wiley Periodicals, Inc.
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complete surgical resection is curative for children with Hepatoblastoma with pure fetal histology a report from the children s oncology group
Journal of Clinical Oncology, 2011Co-Authors: Marcio H Malogolowkin, Rebecka L Meyers, Howard M Katzenstein, Mark Krailo, Jon M Rowland, Joel E Haas, Milton J FinegoldAbstract:Purpose Children with pure fetal histology (PFH) Hepatoblastoma treated with complete surgical resection and minimal adjuvant therapy have been shown to have excellent outcomes when compared with other patients with Hepatoblastoma. We prospectively studied the safety and efficacy of reducing therapy in all children with stage I PFH enrolled onto two consecutive studies. Patients and Methods From August 1989 to December 1992, 9 children with stage I PFH were treated on the Intergroup Hepatoblastoma study INT-0098 and were nonrandomly assigned to receive chemotherapy after surgical resection with single-agent bolus doxorubicin for 3 consecutive days. From March 1999 to November 2006, 16 children with stage I PFH enrolled onto Children's Oncology Group Study P9645 were treated with observation after resection. Central confirmation of the histologic diagnosis by a study group pathologist was mandated. The extent of liver disease was assigned retrospectively according to the pretreatment extent of disease (PRE...
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sodium thiosulfate for protection from cisplatin induced hearing loss
The New England Journal of Medicine, 2018Co-Authors: Penelope Brock, Derek J Roebuck, R Maibach, Margaret Childs, Kaukab Rajput, Michael J Sullivan, Veronique Laithier, Milind Ronghe, Patrizia DallignaAbstract:Abstract Background Cisplatin chemotherapy and surgery are effective treatments for children with standard-risk Hepatoblastoma but may cause considerable and irreversible hearing loss. This trial c...
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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
European Journal of Cancer, 2012Co-Authors: Jozsef Zsiros, Derek J Roebuck, Rudolf Maibach, Laurence Brugieres, Penelope Brock, Bruce Morland, Margaret Child, Michela Casanova, Daniele Pariente, Claudia ParisAbstract:Abstract 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.
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prognostic stratification for children with Hepatoblastoma the siopel experience
European Journal of Cancer, 2012Co-Authors: Rudolf Maibach, Jeanbernard Otte, Derek J Roebuck, Laurence Brugieres, Penelope Brock, Beatriz De Camargo, Jozsef Zsiros, Patrizia Dalligna, Michael Capra, Arthur ZimmermannAbstract:Abstract Purpose To identify factors relevant to long-term outcome in newly diagnosed Hepatoblastoma, and define subgroups for clinical research on tailoring treatment to the individual patient. Patients and methods Between 1995 and 2006 the SIOPEL group conducted two clinical trials which established risk-adapted therapy for Hepatoblastoma patients. Patients were stratified into high-risk (AFP 1,200,000 ng/mL, patient age, platelet count and histology were further explored. The outcome measure was event-free survival (EFS). Results In 541 patients, reduced EFS correlated significantly with AFP 5 years (2.76, 1.68–4.53); borderline with small cell undifferentiated (SCU) histology (2.29, 95% confidence interval 0.91–5.77); but not with PRETEXT III, age 30–60 months, platelet count or V+/P+/E+. By using the significant factors and SCU to stratify the population, we have identified three distinct prognostic groups: PRETEXT I/II/III, and no other factors, have 3 year EFS of 90%, PRETEXT IV and/or multifocal tumour and/or age > 5 years and/or AFP > 1.2 × 106 have 3 year EFS of 71% and SCU and/or AFP Conclusion Prognostic stratification for clinical research on newly diagnosed Hepatoblastoma should take into consideration PRETEXT, metastatic disease, AFP, multifocality, age and SCU histology.
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cisplatin versus cisplatin plus doxorubicin for standard risk Hepatoblastoma
The New England Journal of Medicine, 2009Co-Authors: Giorgio Perilongo, Derek J Roebuck, Rudolf Maibach, Elisabeth Shafford, Laurence Brugieres, Penelope Brock, Bruce Morland, Beatriz De Camargo, Jozsef Zsiros, Arthur ZimmermannAbstract:BACKGROUND: Preoperative cisplatin alone may be as effective as cisplatin plus doxorubicin in standard-risk Hepatoblastoma (a tumor involving three or fewer sectors of the liver that is associated with an alpha-fetoprotein level of >100 ng per milliliter). METHODS: Children with standard-risk Hepatoblastoma who were younger than 16 years of age were eligible for inclusion in the study. After they received one cycle of cisplatin (80 mg per square meter of body-surface area per 24 hours), we randomly assigned patients to receive cisplatin (every 14 days) or cisplatin plus doxorubicin administered in three preoperative cycles and two postoperative cycles. The primary outcome was the rate of complete resection, and the trial was powered to test the noninferiority of cisplatin alone (<10% difference in the rate of complete resection). RESULTS: Between June 1998 and December 2006, 126 patients were randomly assigned to receive cisplatin and 129 were randomly assigned to receive cisplatin plus doxorubicin. The rate of complete resection was 95% in the cisplatin-alone group and 93% in the cisplatin-doxorubicin group in the intention-to-treat analysis (difference, 1.4%; 95% confidence interval [CI], -4.1 to 7.0); these rates were 99% and 95%, respectively, in the per-protocol analysis. Three-year event-free survival and overall survival were, respectively, 83% (95% CI, 77 to 90) and 95% (95% CI, 91 to 99) in the cisplatin group, and 85% (95% CI, 79 to 92) and 93% (95% CI, 88 to 98) in the cisplatin-doxorubicin group (median follow-up, 46 months). Acute grade 3 or 4 adverse events were more frequent with combination therapy (74.4% vs. 20.6%). CONCLUSIONS: As compared with cisplatin plus doxorubicin, cisplatin monotherapy achieved similar rates of complete resection and survival among children with standard-risk Hepatoblastoma. Doxorubicin can be safely omitted from the treatment of standard-risk Hepatoblastoma. (ClinicalTrials.gov number, NCT00003912.)
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guidelines for surgical treatment of Hepatoblastoma in the modern era recommendations from the childhood liver tumour strategy group of the international society of paediatric oncology siopel
European Journal of Cancer, 2005Co-Authors: Piotr Czauderna, Jeanbernard Otte, Daniel C Aronson, Frederic Gauthier, Gordon A Mackinlay, Derek J Roebuck, J Plaschkes, Giorgio PerilongoAbstract:Cisplatin-containing chemotherapy and complete surgical resection are both crucial in the cure of Hepatoblastoma. Radical resection can be obtained either conventionally by partial hepatectomy or with orthotopic liver transplant, but the surgical approach to Hepatoblastoma differs considerably across the world. Our main aim in this paper is to present the surgical recommendations of the Childhood Liver Tumour Strategy Group of the International Society of Paediatric Oncology (SIOPEL), as well as to stimulate international debate on this issue. We discuss biopsy, verification of resectability, resection principles, indications and potential contraindications for orthotopic liver transplant, as well as thoracic surgery for pulmonary metastases. We suggest that heroic liver resections with a high probability of leaving residual tumour should be avoided whenever possible. In such cases primary orthotopic liver transplant should be considered. Superior survival rates in Hepatoblastoma patients who have received a primary transplant after a good response to chemotherapy support the strategy of avoiding partial hepatectomy in cases where radical resection appears difficult and doubtful. We recommend early referral to a transplant surgeon in cases of: (i) multifocal or large solitary PRETEXT IV (PRE Treatment EXTent of disease scoring system) Hepatoblastoma involving all four sectors of the liver and (ii) unifocal, centrally located tumours involving main hilar structures or main hepatic veins. Because complete tumour resection is a prerequisite for cure, any strategy leading to an increased resection rate will result in improved survival. We advise the more frequent use of orthotopic liver transplant, as well as the standardisation of techniques for partial liver resection. These guidelines should not be seen as final, but rather as a starting point for further discussion between the various national and international liver tumour study groups.