Pediatr Blood Cancer 2015;62:715–717
BRIEF REPORT Histone Deacetylase Inhibitor for NUT Midline Carcinoma Ossama M. Maher, MD,1,5* Anthony M. Christensen, PharmD,2 Sireesha Yedururi, Diana Bell, MD, PhD,4 and Nidale Tarek, MD1* NUT Midline carcinoma (NMC) is a rare and invariably fatal poorly differentiated carcinoma characterized by chromosomal rearrangement involving the nuclear protein of the testis (NUT) gene. Current approaches do not provide durable response. We report a case of widely metastatic NMC in a 17-year-old female who, following an initial response to combination chemotherapy devel-
3 MBBS,
oped rapid disease progression. Treatment with vorinostat, a histone deacetylase inhibitor (HDACi) resulted in an objective response, yet she died in less than one year from initial diagnosis. This report shows a potentially promising activity of HDACi in the treatment of NMC that needs further exploration. Pediatr Blood Cancer 2015;62:715– 717. # 2015 Wiley Periodicals, Inc.
Key words: histone deacetylase inhibitor; NUT midline carcinoma
INTRODUCTION NUT midline carcinoma (NMC), first described by Kubonishi in 1991 [1], is an aggressive poorly differentiated squamous cell carcinoma that arises in midline structures primarily the head, neck, and mediastinum. NMC is characterized by rearrangement in the nuclear protein of the testis (NUT) gene [2–4]. The most common rearrangement is a translocation between chromosomes 15 and 19, resulting in the BRD4-NUT fusion oncogene. Diagnosis is usually made by karyotype, FISH or RT-PCR; most recently the development of a NUT-specific monoclonal antibody has provided a specific and sensitive immunohistochemical tool for the diagnosis of NMC [5,6]. The fatal course of the disease stands in need for further understanding this tumor and new therapy development. Newer molecules and/or strategies for treatment are urgently needed. Herein, we present the case of a patient with metastatic NMC that had an objective response to the histone deacetylase inhibitor (HDACi) vorinostat.
OBSERVATION A 17-year-old female presented with a 1-month history of fever, weight loss, generalized bony pain, right mandibular swelling, and shortness of breath. Her initial workup was significant for anemia and elevated lactate dehydrogenase. Imaging studies identified a mass in the left hemithorax, metastatic pleural implants and pleural effusion. Metastatic work up showed diffuse osseous involvement including a large destructive lesion in the right mandible and compression fracture of T8 along with multiple abdominal and mediastinal lymphadenopathy. Bone marrow evaluation showed metastatic disease. A needle biopsy of the mandibular lesion, performed at an outside institution, showed a desmoplastic small round cell tumor. Because of the intractable pain, she received 5 (3 Gy) of 10 planned fractions of radiation therapy to T7-T10 and L2-sacrum prior to presenting to our institution. Pathology specimen reviewed at MD Anderson Cancer Center (MDACC) showed round cell malignant neoplasm, patchy positive for pan-keratin and negative for chromogranin, synaptophysin, desmin, myogenin, pan-melanoma, S-100, CD45, CD99, andWT-1. Immunohistochemical stain for NUT was diffusely positive (Fig.1). Fusion gene analysis was not performed. The morphology of the tumor combined with the immunophenotype
C
2015 Wiley Periodicals, Inc. DOI 10.1002/pbc.25350 Published online 3 January 2015 in Wiley Online Library (wileyonlinelibrary.com).
and clinical characteristics were supportive of NMC. The patient was initiated on docetaxel 90 mg/m2 on day 1, cisplatin 100 mg/m2 on day 1, and 5-fluorouracil 700 mg/m2 with leucovorin 500 mg/m2 continuous infusion for 4 days. Following two cycles of chemotherapy, the tumor in the left hemithorax and the pleural nodules showed moderate response to treatment. The mandibular lesion significantly regressed. A distinct reduction was noted in the size of the supraclavicular, paratracheal, and gastrohepatic lymphadenopathy with sclerotic changes in the metastatic bony lesions indicating treatment effect. After two additional cycles, there was noted progression of the mass in the left hemithorax and increase in size of supraclavicular, paratracheal, gastroheaptic adenopathy and the metastatic lesion in the right mandible (Fig. 2). She was subsequently treated with vorinostat 300 mg daily concomitantly with radiation therapy to the left hemithorax at a total of 30 Gy in 10 fractions. Following completion of radiation therapy, she continued on daily vorinostat 300 mg for 4 weeks. The dose was decreased to 200 mg daily for 1 week then stopped secondary to grade 3 thrombocytopenia (10,000/ml). The response to vorinostat was documented within and outside the radiation field including decrease in the size of right supraclavicular, paratracheal, gastrohepatic lymphadenopathy and reduction of the right mandibular lesion (Fig. 2). The primary chest mass and osseous metastatic disease were stable 7 weeks following initiation of vorinostat. The patient
1
Department of Pediatrics, University of Texas, MD Anderson Cancer Center, Houston, Texas; 2Department of Pharmacy Clinical Programs, University of Texas, MD Anderson Cancer Center, Houston, Texas; 3 Department of Radiology, University of Texas, MD Anderson Cancer Center, Houston, Texas; 4Department of Pathology, University of Texas, MD Anderson Cancer Center, Houston, Texas; 5Department of Pediatrics, National Cancer Institute, Cairo University, Cairo, Egypt The authors have no financial relationships relevant to this article to disclose. Conflict of interest: Nothing to declare. Correspondence to: Ossama Maher and Nidale Tarek, Department of Pediatrics, University of Texas, MD 1515 Holcombe, Unit 87, Houston, TX 77030. E-mail: [email protected]; [email protected]
Received 12 July 2014; Accepted 12 October 2014
716
Maher et al.
Fig. 1. Hematoxylin and eosin (10X) showing an undifferentiated carcinoma; the cells have large nuclei with prominent nucleoli and scant cytoplasm (A). Immunohistochemistry with NUT- specific monoclonal antibody (nuclear staining) confirming the diagnosis of NUT mid line carcinoma (B).
subsequently died from disease progression and severe respiratory compromise 10 months after diagnosis and 1 month after vorinostat was stopped.
DISCUSSION NMC is a highly aggressive and fatal malignancy with no sex, racial, or age predilection [7,8]. Most patients present with
unresectable disease and widespread metastasis. The average survival time is less than one year despite aggressive multimodality treatment [9]. These tumors are often mistaken for head/neck or lung carcinomas, pediatric small round cell tumors, or highgrade hematologic malignancies. The recently described immunohistochemistry method using a newly available monoclonal antibody to the NUT protein is a promising tool for accurate diagnosis [5].
Fig. 2. Axial CT scan of the neck with contrast shows a large destructive lesion in the mandible following two cycles of chemotherapy (A) with interval progression after four cycles (B) and reduction in the size of the mass after treatment with 7-week of vorinostat (C). Similarly, (D) CT scan of the abdomen with contrast showing metastatic gastrohepatic lymph node with interval progression following 4 cycles (E) and a partial response to single agent vorinostat (F). Notably, both tumor sites were not involved in the radiation field. Pediatr Blood Cancer DOI 10.1002/pbc
HDACi for NUT Midline Carcinoma NUT gene translocations generate BRD-NUT fusion proteins that arrest squamous cell differentiation through decrease histone acetylation and transcriptional repression [10]. Characterization of the fusion gene is not required for the diagnosis, but is recommended. NUT-variant carcinomas lacking BRD4 rearrangement appear more differentiated, compared to BRD4-NUT tumors, and are conceivably less aggressive [8,9]. New potential treatments using a small molecule bromodomain inhibitor, which inhibits binding of BRD-NUT to chromatin resulting in arrest of proliferation and cellular differentiation [11], are in early stages of development (NCT01587703, NCT01987362). Recent preclinical data explored the role of HDACi in NMC and showed promising results by inducing differentiation of tumor cells and suppression of tumor growth in xenograft models [10]. An objective response was as well documented in a child following five weeks of therapy with vorinostat [10]. Our case is the second described case of metastatic NMC showing objective response to HDACi, vorinostat. The decision of combining vorinostat 300 mg daily with radiation therapy was based on its potential role in the treatment of NMC [10], its radiosensitizer activity [12,13] and the described response to radiation therapy [8]. Similar to the prior reported case, treatment was stopped secondary to adverse effects. An intermittent schedule for vorinostat, as previously described [14,15], may be considered for better tolerance. Further prospective approaches to treat NMC with HDAC inhibition, alone or in combination are warranted. Additional studies to identify molecular alterations are indicated to guide future treatments.
Pediatr Blood Cancer DOI 10.1002/pbc
717
REFERENCES 1. Kubonishi I, Takehara N, Iwata J, Sonobe H, Ohtsuki Y, Abe T, Miyoshi I. Novel t(15;19)(q15;p13) chromosome abnormality in a thymic carcinoma. Cancer Res 1991;51:3327–3328. 2. French CA. Pathogenesis of NUT midline carcinoma. Annu Rev Pathol 2012;7:247–265. 3. French CA. The importance of diagnosing NUT midline carcinoma. Head Neck Pathol 2013;7:11–16. 4. Stelow EB. A review of NUT midline carcinoma. Head Neck Pathol 2011;5:31–35. 5. Haack H, Johnson LA, Fry CJ, Crosby K, Polakiewicz RD, Stelow EB, Hong SM, Schwartz BE, Cameron MJ, Rubin MA, Chang MC, Aster JC, French CA. Diagnosis of NUT midline carcinoma using a NUTspecific monoclonal antibody. Am J Surg Pathol 2009;33:984–991. 6. Evans AG, French CA, Cameron MJ, Fletcher CD, Jackman DM, Lathan CS, Sholl LM. Pathologic characteristics of NUT midline carcinoma arising in the mediastinum. Am J Surg Pathol 2012;36:1222– 1227. 7. French CA. NUT midline carcinoma. Cancer Genet Cytogenet 2010;203:16–20. 8. Bauer DE, Mitchell CM, Strait KM, Lathan CS, Stelow EB, Luer SC, Muhammed S, Evans AG, Sholl LM, Rosai J, Giraldi E, Oakley RP, Rodriguez-Galindo C, London WB, Sallan SE, Bradner JE, French CA. Clinicopathologic features and long-term outcomes of NUT midline carcinoma. Clin Cancer Res 2012;18:5773–5779. 9. French CA, Kutok JL, Faquin WC, Toretsky JA, Antonescu CR, Griffin CA, Nose V, Vargeas SO, Moschovi M, Tzortzatou-Stathopoulou F, Miyoshi I, Perez-Atayde AR, Aster JC, Fletcher JA. Midline carcinoma of children and young adults with NUT rearrangement. J Clin Oncol 2004;22:4135–4139. 10. Schwartz BE, Hofer MD, Lemieux ME, Bauer DE, Cameron MJ, West NH, Agoston ES, Reynoird N, Khochbin S, Ince TA, Christie A, Janeway KA, Vargas SO, Perez-Atayde AR, Aster JC, Sallan SE, Kung AL, Bradner JE, French CA. Differentiation of NUT midline carcinoma by epigenomic reprogramming. Cancer Res 2011;71:2686–2696. 11. Filippakopoulos P, Qi J, Picaud S, Shen Y, Smith WB, Fedorov O, Morse EM, Keates T, Hickman TT, Felletar I, Philpott M, Munro S, McKeown MR, Wang Y, Christie AL, West N, Cameron MJ, Schwartz B, Heightman TD, La Thanque N, French CA, Wiest O, Kung AL, Knapp S, Bradner JE. Selective inhibition of BET bromodomains. Nature 2010;468:1067–1073. 12. Munshi A, Tanaka T, Hobbs ML, Tucker SL, Richon VM, Meyn RE. Vorinostat, a histone deacetylase inhibitor, enhances the response of human tumor cells to ionizing radiation through prolongation of gamma-H2AX foci. Mol Cancer Ther 2006;5:1967–1974. 13. Ree AH, Dueland S, Folkvord S, Hole KH, Seierstad T, Johansen M, Abrahamsen TW, Flatmark K. Vorinostat, a histone deacetylase inhibitor, combined with pelvic palliative radiotherapy for gastrointestinal carcinoma: the Pelvic Radiation and Vorinostat (PRAVO) phase 1 study. Lancet Oncol 2010;11:459–464. 14. Hummel TR, Wagner L, Ahern C, Fouladi M, Reid J, McGovern RM, Ames MM, Gilberston RJ, Horton T, Ingle AM, Weigel B, Blaney SM. A pediatric phase 1 trial of vorinostat and temozolomide in relapsed or refractory primary brain or spinal cord tumors: a Children’s Oncology Group phase 1 consortium study. Pediatr Blood Cancer 2013;60:1452–1457. 15. Fouladi M, Park J, Stewart CF, Gilberston RJ, Schaiquevich P, Sun J, Reid JM, Ames MM, Speights R, Ingle AM, Zwiebel J, Blaney SM, Adamson PC. Pediatric phase I trial and pharmacokinetic study of vorinostat: a Children’s Oncology Group phase I consortium report. J Clin Oncol 2010;28:3623–3629.
BRIEF REPORT Histone Deacetylase Inhibitor for NUT Midline Carcinoma Ossama M. Maher, MD,1,5* Anthony M. Christensen, PharmD,2 Sireesha Yedururi, Diana Bell, MD, PhD,4 and Nidale Tarek, MD1* NUT Midline carcinoma (NMC) is a rare and invariably fatal poorly differentiated carcinoma characterized by chromosomal rearrangement involving the nuclear protein of the testis (NUT) gene. Current approaches do not provide durable response. We report a case of widely metastatic NMC in a 17-year-old female who, following an initial response to combination chemotherapy devel-
3 MBBS,
oped rapid disease progression. Treatment with vorinostat, a histone deacetylase inhibitor (HDACi) resulted in an objective response, yet she died in less than one year from initial diagnosis. This report shows a potentially promising activity of HDACi in the treatment of NMC that needs further exploration. Pediatr Blood Cancer 2015;62:715– 717. # 2015 Wiley Periodicals, Inc.
Key words: histone deacetylase inhibitor; NUT midline carcinoma
INTRODUCTION NUT midline carcinoma (NMC), first described by Kubonishi in 1991 [1], is an aggressive poorly differentiated squamous cell carcinoma that arises in midline structures primarily the head, neck, and mediastinum. NMC is characterized by rearrangement in the nuclear protein of the testis (NUT) gene [2–4]. The most common rearrangement is a translocation between chromosomes 15 and 19, resulting in the BRD4-NUT fusion oncogene. Diagnosis is usually made by karyotype, FISH or RT-PCR; most recently the development of a NUT-specific monoclonal antibody has provided a specific and sensitive immunohistochemical tool for the diagnosis of NMC [5,6]. The fatal course of the disease stands in need for further understanding this tumor and new therapy development. Newer molecules and/or strategies for treatment are urgently needed. Herein, we present the case of a patient with metastatic NMC that had an objective response to the histone deacetylase inhibitor (HDACi) vorinostat.
OBSERVATION A 17-year-old female presented with a 1-month history of fever, weight loss, generalized bony pain, right mandibular swelling, and shortness of breath. Her initial workup was significant for anemia and elevated lactate dehydrogenase. Imaging studies identified a mass in the left hemithorax, metastatic pleural implants and pleural effusion. Metastatic work up showed diffuse osseous involvement including a large destructive lesion in the right mandible and compression fracture of T8 along with multiple abdominal and mediastinal lymphadenopathy. Bone marrow evaluation showed metastatic disease. A needle biopsy of the mandibular lesion, performed at an outside institution, showed a desmoplastic small round cell tumor. Because of the intractable pain, she received 5 (3 Gy) of 10 planned fractions of radiation therapy to T7-T10 and L2-sacrum prior to presenting to our institution. Pathology specimen reviewed at MD Anderson Cancer Center (MDACC) showed round cell malignant neoplasm, patchy positive for pan-keratin and negative for chromogranin, synaptophysin, desmin, myogenin, pan-melanoma, S-100, CD45, CD99, andWT-1. Immunohistochemical stain for NUT was diffusely positive (Fig.1). Fusion gene analysis was not performed. The morphology of the tumor combined with the immunophenotype
C
2015 Wiley Periodicals, Inc. DOI 10.1002/pbc.25350 Published online 3 January 2015 in Wiley Online Library (wileyonlinelibrary.com).
and clinical characteristics were supportive of NMC. The patient was initiated on docetaxel 90 mg/m2 on day 1, cisplatin 100 mg/m2 on day 1, and 5-fluorouracil 700 mg/m2 with leucovorin 500 mg/m2 continuous infusion for 4 days. Following two cycles of chemotherapy, the tumor in the left hemithorax and the pleural nodules showed moderate response to treatment. The mandibular lesion significantly regressed. A distinct reduction was noted in the size of the supraclavicular, paratracheal, and gastrohepatic lymphadenopathy with sclerotic changes in the metastatic bony lesions indicating treatment effect. After two additional cycles, there was noted progression of the mass in the left hemithorax and increase in size of supraclavicular, paratracheal, gastroheaptic adenopathy and the metastatic lesion in the right mandible (Fig. 2). She was subsequently treated with vorinostat 300 mg daily concomitantly with radiation therapy to the left hemithorax at a total of 30 Gy in 10 fractions. Following completion of radiation therapy, she continued on daily vorinostat 300 mg for 4 weeks. The dose was decreased to 200 mg daily for 1 week then stopped secondary to grade 3 thrombocytopenia (10,000/ml). The response to vorinostat was documented within and outside the radiation field including decrease in the size of right supraclavicular, paratracheal, gastrohepatic lymphadenopathy and reduction of the right mandibular lesion (Fig. 2). The primary chest mass and osseous metastatic disease were stable 7 weeks following initiation of vorinostat. The patient
1
Department of Pediatrics, University of Texas, MD Anderson Cancer Center, Houston, Texas; 2Department of Pharmacy Clinical Programs, University of Texas, MD Anderson Cancer Center, Houston, Texas; 3 Department of Radiology, University of Texas, MD Anderson Cancer Center, Houston, Texas; 4Department of Pathology, University of Texas, MD Anderson Cancer Center, Houston, Texas; 5Department of Pediatrics, National Cancer Institute, Cairo University, Cairo, Egypt The authors have no financial relationships relevant to this article to disclose. Conflict of interest: Nothing to declare. Correspondence to: Ossama Maher and Nidale Tarek, Department of Pediatrics, University of Texas, MD 1515 Holcombe, Unit 87, Houston, TX 77030. E-mail: [email protected]; [email protected]
Received 12 July 2014; Accepted 12 October 2014
716
Maher et al.
Fig. 1. Hematoxylin and eosin (10X) showing an undifferentiated carcinoma; the cells have large nuclei with prominent nucleoli and scant cytoplasm (A). Immunohistochemistry with NUT- specific monoclonal antibody (nuclear staining) confirming the diagnosis of NUT mid line carcinoma (B).
subsequently died from disease progression and severe respiratory compromise 10 months after diagnosis and 1 month after vorinostat was stopped.
DISCUSSION NMC is a highly aggressive and fatal malignancy with no sex, racial, or age predilection [7,8]. Most patients present with
unresectable disease and widespread metastasis. The average survival time is less than one year despite aggressive multimodality treatment [9]. These tumors are often mistaken for head/neck or lung carcinomas, pediatric small round cell tumors, or highgrade hematologic malignancies. The recently described immunohistochemistry method using a newly available monoclonal antibody to the NUT protein is a promising tool for accurate diagnosis [5].
Fig. 2. Axial CT scan of the neck with contrast shows a large destructive lesion in the mandible following two cycles of chemotherapy (A) with interval progression after four cycles (B) and reduction in the size of the mass after treatment with 7-week of vorinostat (C). Similarly, (D) CT scan of the abdomen with contrast showing metastatic gastrohepatic lymph node with interval progression following 4 cycles (E) and a partial response to single agent vorinostat (F). Notably, both tumor sites were not involved in the radiation field. Pediatr Blood Cancer DOI 10.1002/pbc
HDACi for NUT Midline Carcinoma NUT gene translocations generate BRD-NUT fusion proteins that arrest squamous cell differentiation through decrease histone acetylation and transcriptional repression [10]. Characterization of the fusion gene is not required for the diagnosis, but is recommended. NUT-variant carcinomas lacking BRD4 rearrangement appear more differentiated, compared to BRD4-NUT tumors, and are conceivably less aggressive [8,9]. New potential treatments using a small molecule bromodomain inhibitor, which inhibits binding of BRD-NUT to chromatin resulting in arrest of proliferation and cellular differentiation [11], are in early stages of development (NCT01587703, NCT01987362). Recent preclinical data explored the role of HDACi in NMC and showed promising results by inducing differentiation of tumor cells and suppression of tumor growth in xenograft models [10]. An objective response was as well documented in a child following five weeks of therapy with vorinostat [10]. Our case is the second described case of metastatic NMC showing objective response to HDACi, vorinostat. The decision of combining vorinostat 300 mg daily with radiation therapy was based on its potential role in the treatment of NMC [10], its radiosensitizer activity [12,13] and the described response to radiation therapy [8]. Similar to the prior reported case, treatment was stopped secondary to adverse effects. An intermittent schedule for vorinostat, as previously described [14,15], may be considered for better tolerance. Further prospective approaches to treat NMC with HDAC inhibition, alone or in combination are warranted. Additional studies to identify molecular alterations are indicated to guide future treatments.
Pediatr Blood Cancer DOI 10.1002/pbc
717
REFERENCES 1. Kubonishi I, Takehara N, Iwata J, Sonobe H, Ohtsuki Y, Abe T, Miyoshi I. Novel t(15;19)(q15;p13) chromosome abnormality in a thymic carcinoma. Cancer Res 1991;51:3327–3328. 2. French CA. Pathogenesis of NUT midline carcinoma. Annu Rev Pathol 2012;7:247–265. 3. French CA. The importance of diagnosing NUT midline carcinoma. Head Neck Pathol 2013;7:11–16. 4. Stelow EB. A review of NUT midline carcinoma. Head Neck Pathol 2011;5:31–35. 5. Haack H, Johnson LA, Fry CJ, Crosby K, Polakiewicz RD, Stelow EB, Hong SM, Schwartz BE, Cameron MJ, Rubin MA, Chang MC, Aster JC, French CA. Diagnosis of NUT midline carcinoma using a NUTspecific monoclonal antibody. Am J Surg Pathol 2009;33:984–991. 6. Evans AG, French CA, Cameron MJ, Fletcher CD, Jackman DM, Lathan CS, Sholl LM. Pathologic characteristics of NUT midline carcinoma arising in the mediastinum. Am J Surg Pathol 2012;36:1222– 1227. 7. French CA. NUT midline carcinoma. Cancer Genet Cytogenet 2010;203:16–20. 8. Bauer DE, Mitchell CM, Strait KM, Lathan CS, Stelow EB, Luer SC, Muhammed S, Evans AG, Sholl LM, Rosai J, Giraldi E, Oakley RP, Rodriguez-Galindo C, London WB, Sallan SE, Bradner JE, French CA. Clinicopathologic features and long-term outcomes of NUT midline carcinoma. Clin Cancer Res 2012;18:5773–5779. 9. French CA, Kutok JL, Faquin WC, Toretsky JA, Antonescu CR, Griffin CA, Nose V, Vargeas SO, Moschovi M, Tzortzatou-Stathopoulou F, Miyoshi I, Perez-Atayde AR, Aster JC, Fletcher JA. Midline carcinoma of children and young adults with NUT rearrangement. J Clin Oncol 2004;22:4135–4139. 10. Schwartz BE, Hofer MD, Lemieux ME, Bauer DE, Cameron MJ, West NH, Agoston ES, Reynoird N, Khochbin S, Ince TA, Christie A, Janeway KA, Vargas SO, Perez-Atayde AR, Aster JC, Sallan SE, Kung AL, Bradner JE, French CA. Differentiation of NUT midline carcinoma by epigenomic reprogramming. Cancer Res 2011;71:2686–2696. 11. Filippakopoulos P, Qi J, Picaud S, Shen Y, Smith WB, Fedorov O, Morse EM, Keates T, Hickman TT, Felletar I, Philpott M, Munro S, McKeown MR, Wang Y, Christie AL, West N, Cameron MJ, Schwartz B, Heightman TD, La Thanque N, French CA, Wiest O, Kung AL, Knapp S, Bradner JE. Selective inhibition of BET bromodomains. Nature 2010;468:1067–1073. 12. Munshi A, Tanaka T, Hobbs ML, Tucker SL, Richon VM, Meyn RE. Vorinostat, a histone deacetylase inhibitor, enhances the response of human tumor cells to ionizing radiation through prolongation of gamma-H2AX foci. Mol Cancer Ther 2006;5:1967–1974. 13. Ree AH, Dueland S, Folkvord S, Hole KH, Seierstad T, Johansen M, Abrahamsen TW, Flatmark K. Vorinostat, a histone deacetylase inhibitor, combined with pelvic palliative radiotherapy for gastrointestinal carcinoma: the Pelvic Radiation and Vorinostat (PRAVO) phase 1 study. Lancet Oncol 2010;11:459–464. 14. Hummel TR, Wagner L, Ahern C, Fouladi M, Reid J, McGovern RM, Ames MM, Gilberston RJ, Horton T, Ingle AM, Weigel B, Blaney SM. A pediatric phase 1 trial of vorinostat and temozolomide in relapsed or refractory primary brain or spinal cord tumors: a Children’s Oncology Group phase 1 consortium study. Pediatr Blood Cancer 2013;60:1452–1457. 15. Fouladi M, Park J, Stewart CF, Gilberston RJ, Schaiquevich P, Sun J, Reid JM, Ames MM, Speights R, Ingle AM, Zwiebel J, Blaney SM, Adamson PC. Pediatric phase I trial and pharmacokinetic study of vorinostat: a Children’s Oncology Group phase I consortium report. J Clin Oncol 2010;28:3623–3629.
