Pediatr Blood Cancer 2015;62:1072–1074
BRIEF REPORT PD0332991 (Palbociclib) for Treatment of Pediatric Intracranial Growing Teratoma Syndrome Kris Ann P. Schultz, MD,1* Joseph Petronio, MD,2 Anne Bendel, MD,1 Richard Patterson, MD,3 and David J. Vaughn, MD4 Growing teratoma syndrome is characterized by growth of mature teratoma elements of a mixed germ cell tumor despite resolution of immature/malignant elements with administration of chemotherapy. Surgical resection is the only known cure for growing teratoma syndrome but in the brain, complete resection may be impossible. In these instances, mature teratoma, although histologically benign,
may be fatal. In this report, we present the case of a child with a large, rapidly growing, unresectable pineal region growing teratoma. PD0332991 was administered with stabilization of the solid, enhancing components of the mass. Minimal adverse effects were noted. Pediatr Blood Cancer 2015;62:1072–1074. # 2014 Wiley Periodicals, Inc.
Key words: brain tumor; cyclin-dependent kinase; germ cell tumor; teratoma
INTRODUCTION Growing teratoma syndrome is a rare condition that can be seen in the setting of extracranial or intracranial germ cell tumors. Growing teratoma syndrome usually is seen in the setting of lesions metastatic from nonseminomatous germ cell tumors, usually from primary lesions in the ovary or testis. Growing teratoma syndrome may occur in up to 6.5% of patients with intracranial germ cell tumors [1]. Growing teratoma syndrome is characterized by growth of mature teratoma elements despite resolution of immature/malignant elements with administration of chemotherapy. Criteria for growing teratoma syndrome are: (i) normalization of elevated serum tumor markers; (ii) tumor growth during or after chemotherapy for nonseminomatous germ cell tumor; and (iii) the histologic presence of only mature teratoma at tumor resection [2,3]. Surgical resection is the only known cure for growing teratoma syndrome [4] but in the brain, complete resection may be impossible. Complications of growing teratoma syndrome usually arise from mass effect on adjacent structures [5]. In these instances, mature teratoma, although histologically benign, may be fatal [1].
CASE REPORT A 5-year-old presented with upward gaze paresis and headache. MRI scan showed a large mixed cystic and solid tumor arising from the pineal region, most consistent with germ cell tumor. Serum AFP was mildly elevated at 17 ng/ml. Serum beta HCG, CEA and CSF AFP, beta-HCG and CEA were normal. No other source of elevated AFP was identified. Biopsy showed mature CNS tissue and cytokeratin-positive squamous epithelium, consistent with mature teratoma. Serum and CSF tumor markers were repeated postoperatively and showed a serum AFP of 38 ng/ml and CSF AFP of 39 ng/ml thus the patient was diagnosed with intracranial nongerminomatous germ cell tumor. Cisplatin-based chemotherapy was initiated. MRI scan performed at the start of the third cycle of chemotherapy showed enlargement of the mixed cystic and solid mass concerning for tumor progression versus growing teratoma syndrome. Tumor markers were normal, confirming the diagnosis of intracranial growing teratoma syndrome. Chemotherapy was discontinued. Cytogenetic analysis of a posttreatment tumor biopsy C
showed 47, XY, þX, chromosome t(11;16) (q23;24) in all metaphase cells studied. Constitutional cytogenetics were normal. The patient underwent successive craniotomies in an attempt to debulk the tumor (Fig. 1) but unfortunately his tumor was not able to be completely resected and it continued to grow causing compression on critical areas and neurologic symptoms. The patient also developed extensive central venous sinus thrombosis (CVST) following multiple craniotomies. A single dose of interferon alpha-2b was administered but the patient developed respiratory distress requiring hospitalization thus interferon was discontinued. Based on the report by Vaughn et al. [6] showing stabilization of extracranial growing teratoma syndrome with PD0332991 (Palbociclib; Pfizer, New York, NY), a request was made to obtain permission for single patient use of PD0332991. As a condition of therapy, a previous biopsy specimen was tested for the presence of retinoblastoma protein (pRB) and was found to be positive, similar to the adult cases in the initial series. PD0332991 was initiated at a dose of 75 mg orally days 1–21 of each 28 day cycle. MRI showed stabilization of overall tumor size for approximately 3 months following initiation. Since that time, there has been ongoing stabilization of the enhancing, solidappearing areas which intraoperatively correlate to areas of solid, vascularized tissue. There has been slow progression of multiple nonenhancing, hypointense areas which appear cyst-like on MRI but intraoperatively contain mucoid, sebum-like substance. 1
Cancer and Blood Disorders, Children’s Hospitals and Clinics of Minnesota, Minneapolis, Minnesota; 2Neurosurgery, Children’s Hospitals and Clinics of Minnesota, Minneapolis, Minnesota; 3 Radiology, Children’s Hospitals and Clinics of Minnesota, Minneapolis, Minnesota; 4Hematology/Oncology, University of Pennsylvania, Philadelphia, Pennsylvania Conflict of interest: Nothing to declare. Palbociclib (PD033291) is an investigational compound and it is not approved for the treatment of this condition. Correspondence to: Kris Ann P. Schultz, Cancer and Blood Disorders, International OTST Registry, Children’s Hospital and Clinics of MN, 2530 Chicago Ave. S. CSC-175, Minneapolis, MN 55404. E-mail: [email protected]
Received 29 May 2014; Accepted 8 October 2014
2014 Wiley Periodicals, Inc. DOI 10.1002/pbc.25338 Published online 21 November 2014 in Wiley Online Library (wileyonlinelibrary.com).
Palbociclib for Intracranial Growing Teratoma
1073
Fig. 1. Radiographs showing: (A) Large pineal region germ cell tumor; (B) Increase in size of tumor despite normalization of tumor markers following initiation of chemotherapy and three successive craniotomies for partial debulking; (C) Growth of solid, enhancing components despite additional surgical debulking; (D) Slight decrease in size of tumor following initiation of PD0332991; (E) Stabilization of solid, enhancing components and growth of cystic components while on PD0332991; (F) Postcontrast MRI following thermoablation and 12 cycles of PD0332991.
Clinically, the patient has done well with significant improvement in his overall function and no further need for urgent surgical intervention for neurologic symptoms. Laser-interstitial thermal therapy has been performed twice and was well tolerated with reduction in tumor bulk following thermoablation. This stabilization was a change from his previous course during which he demonstrated tumor growth and clinical decline. Administration of the medication over 22 cycles has been well tolerated with uncomplicated neutropenia and fatigue as the only adverse events attributed to the medication. Height velocity is slowed although it remains unclear if this is due to medication, tumor or surgery. Recurrent CVST occurred, likely related to tumor and surgery. No grade III or IV side effects attributable to PD0332991 have been observed in this patient who remains alive and well 30 months after his diagnosis. Administration is ongoing and at least one additional laser thermoablation is planned.
DISCUSSION Oral PD0332991 is a selective reversible inhibitor of cyclindependent kinases (CDK) 4 and 6. Inhibition of CDK 4/6 blocks DNA synthesis by prohibiting progression of the cell cycle from G1 to S phase. Data from nonclinical studies indicate that PD0332991 may have cytoreductive as well as cytostatic effects on tumor cells. This oral kinase inhibitor has been utilized in adult trials including patients with advanced breast cancer [7], liposarcoma [8] and mantle cell lymphoma [9]. Mature teratomas express high levels of pRB. Cyclin dependent kinase 4/6 (CDK 4/6) stimulates cell growth by phophorylating pRB [6]. The use of PD0332991 in three adult patients with mature growing teratoma syndrome has been described by Vaughn et al. [6]. Pediatr Blood Cancer DOI 10.1002/pbc
Parrish et al. reported that the blood–brain barrier efflux pump may result in decreased brain penetration of PD0332991 in a murine model [10]. In our patient, however, it is possible that his blood–brain barrier was significantly disrupted by previous surgeries resulting improved distribution and increased efficacy. Also, the murine model may not be representative of the physiology of this pediatric germ cell tumor. In this report, we cannot rule out that the tumor may have stabilized without additional intervention; however, the history of growth and increased clinical symptoms until initiation of PD0332991 suggests the clinical course was stabilized by PD0332991. It is difficult to predict the growth of mature teratomas and thus difficult to determine the effect of an intervention on the natural history of growing teratoma. Following intervention, the patient’s clinical course and tumor appearance stabilized, however, in order to determine if this indicates a direct effect of the PD0332991, additional biologic, translational and clinical studies are needed. It is important to note that the biology of germ cell tumors is heterogeneous [11]. This pineal region tumor showed a gain of X which has been described in pineal germ cell tumor [12,13] and a chromosome t(11;16) translocation of uncertain clinical significance. The application of this case to children or adults with other brain tumors is unclear. Other strategies may be considered in the treatment of growing teratoma syndrome. These include interferon [14] and radiation. Radiation is a standard treatment of nongerminomatous germ cell tumors [15–17] but was not utilized in this case due to normalization of tumor markers and concern for the development of malignant transformation of the residual teratoma [18]. Radiation may be necessary in the future pending his clinical course.
1074
Schultz et al.
We report the use of PD0332991 in a pediatric patient with an intracranial teratoma. Importantly, PD0332991 appeared to cause stabilization of the vascularized, enhancing components of the tumor; however, the nonenhancing, hypointense areas continued to slowly progress and required additional treatment. The oral regimen was well tolerated. Although there was not complete radiographic stabilization, the partial stabilization allowed for a longer interval between surgical procedures and thus an overall more stable clinical course. Further investigation of the use of PD0332991in children with growing teratoma syndrome and potentially other refractory germ cell tumors may be warranted.
REFERENCES
8.
9.
10.
11.
12.
13. 14.
1. Kim CY, Choi JW, Lee JY, Kim SK, Wang KC, Park SH, Choe G, Ahn HS, Kim IH, Cho BK. Intracranial growing teratoma syndrome: Clinical characteristics andtreatment strategy. J Neurooncol 2011;101:109–115. 2. Logothetis CJ, Samuels ML, Trindade A, Johnson DE. The growing teratoma syndrome. Cancer 1982;50:1629–1635. 3. Lee DJ, Djaladat H, Tadros NN, Movassaghi M, Tejura T, Duddalwar V, Daneshmand S. Growing teratoma syndrome: Clinical and radiographic characteristics. Int J Urol 2014;21:905–908. 4. Denaro L, Pluchinotta F, Faggin R, Manara R, Calderone M, Viscardi E, Gardiman M, Rossetto M, Perilongo G, d’Avella D. What’s growing on? The growing teratoma syndrome. Acta Neurochir (Wien) 2010;152:1943–1946. 5. Byrd K, Stany MP, Herbold NC, Leath CA, 3rd, Hamilton CA. G rowing teratoma syndrome: Brief communication and algorithm for management. Aust N Z J Obstet Gynaecol 2013;53:318–321. 6. Vaughn DJ, Flaherty K, Lal P, Gallagher M, O’Dwyer P, Wilner K, Chen I, Schwartz G. Treatment of growing teratoma syndrome. N Engl J Med 2009;360:423–424. 7. Finn RS, Crown JP, Lang I, Boer K, Bondarenko IM, Kulyk SO, Ettl J, Patel T, Schmidt M, Shparyk Y, Thummala AR, Voytko NL, Breazna A, Kim ST, Randolph S, Slamon DJ. Results of a randomized phase 2 study of PD 0332991, a cyclin-dependent kinase (CDK) 4/6 inhibitor, in combination with Letrozole vs
Pediatr Blood Cancer DOI 10.1002/pbc
15.
16.
17.
18.
Letrozole alone for first-line treatment of ER+/HER2- advanced breast cancer (BC). Cancer Res 2012:72: Abstract nr S1–S6. Dickson MA, Tap WD, Keohan ML, D’Angelo SP, Gounder MM, Antonescu CR, Landa J, Qin LX, Rathbone DD, Condy MM, Ustoyev Y, Crago AM, Singer S, Schwartz GK. Phase II trial of the CDK4 inhibitor PD0332991 in patients with advanced CDK4-amplified well-differentiated or dedifferentiated liposarcoma. J Clin Oncol 2013;31:2024–2028. Leonard JP, LaCasce AS, Smith MR, Noy A, Chirieac LR, Rodig SJ, Yu JQ, Vallabhajosula S, Schoder H, English P, Neuberg DS, Martin P, Millenson MM, Ely SA, Courtney R, Shaik N, Wilner KD, Randolph S, Van den Abbeele AD, Chen-Kiang SY, Yap JT, Shapiro GI. Selective CDK4/6 inhibition with tumor responses by PD0332991 in patients with mantle cell lymphoma. Blood 2012;119:4597–4607. Parrish KE, Pokorny JL, Mittapalli RK, Bakken K, Sarkaria JN, Elmquist WF. BBB efflux pump activity limits brain 201 penetration of palbocicli (PD0332991) in glioblastoma. Mol Cancer Ther 2013;12:C81. Hersmus R, de Leeuw BH, Wolffenbuttel KP, Drop SL, Oosterhuis JW, Cools M, Looijenga LH. New insights into type II germ cell tumor pathogenesis based on studies of patients with various forms of disorders of sex development (DSD). Mol Cell Endocrinol 2008;291:1–10. Yu IT, Griffin CA, Phillips PC, Strauss LC, Perlman EJ. Numerical sex chromosomal abnormalities in pineal teratomas by cytogenetic analysis and fluorescence in situ hybridization. Lab Invest 1995;72:419– 423. Casalone R, Righi R, Granata P, Portentoso P, Minelli E, Meroni, Solero CL, Allegranza A. Cerebral germ cell tumor and XXY karyotype. Cancer Genet Cytogenet 1994;74:25–29. Ornadel D, Wilson A, Trask C, Ledermann J. Remission of recurrent mature teratoma with interferon therapy. JR Soc Med 1995;88:533P–534P. Khatua S, Dhall G, O’Neil S, Jubran R, Villablanca JG, Marachelian A, Nastia A, Lavey R, Olch AJ, Gonzalez I, Gilles F, Nelson M, Panigrahy A, McComb G, Krieger M, Fan J, Sposto R, Finlay JL. Treatment of primary CNS germinomatous germ cell tumors with chemotherapy prior to reduced dose whole ventricular and local boost irradiation. Pediatr Blood Cancer 2010;55:42–46. Calaminus G, Kortmann R, Worch J, Nicholson JC, Alapetite C, Garre ML, Patte C, Ricardi U, Saran F, Frappaz D. SIOP CNS GCT 96: Final report of outcome of a prospective, multinational nonrandomized trial for children and adults with intracranial germinoma, comparing craniospinal irradiation alone with chemotherapy followed by focal primary site irradiation for patients with localized disease. Neuro Oncol 2013;15:788–796. Kretschmar C, Kleinberg L, Greenberg M, Burger P, Holmes E, Wharam M. Pre-radiation chemotherapy with response-based radiation therapy in children with central nervous system germ cell tumors: A report from the Children’s Oncology Group. Pediatr Blood Cancer 2007;48:285–291. Glass T, Cochrane DD, Rassekh SR, Goddard K, Hukin J. Growing teratoma syndrome in intracranial nongerminomatous germ cell tumors (iNGGCTs): A risk for secondary malignant transformation-a report of two cases. Childs Nerv Syst 2014;30:953–959.
BRIEF REPORT PD0332991 (Palbociclib) for Treatment of Pediatric Intracranial Growing Teratoma Syndrome Kris Ann P. Schultz, MD,1* Joseph Petronio, MD,2 Anne Bendel, MD,1 Richard Patterson, MD,3 and David J. Vaughn, MD4 Growing teratoma syndrome is characterized by growth of mature teratoma elements of a mixed germ cell tumor despite resolution of immature/malignant elements with administration of chemotherapy. Surgical resection is the only known cure for growing teratoma syndrome but in the brain, complete resection may be impossible. In these instances, mature teratoma, although histologically benign,
may be fatal. In this report, we present the case of a child with a large, rapidly growing, unresectable pineal region growing teratoma. PD0332991 was administered with stabilization of the solid, enhancing components of the mass. Minimal adverse effects were noted. Pediatr Blood Cancer 2015;62:1072–1074. # 2014 Wiley Periodicals, Inc.
Key words: brain tumor; cyclin-dependent kinase; germ cell tumor; teratoma
INTRODUCTION Growing teratoma syndrome is a rare condition that can be seen in the setting of extracranial or intracranial germ cell tumors. Growing teratoma syndrome usually is seen in the setting of lesions metastatic from nonseminomatous germ cell tumors, usually from primary lesions in the ovary or testis. Growing teratoma syndrome may occur in up to 6.5% of patients with intracranial germ cell tumors [1]. Growing teratoma syndrome is characterized by growth of mature teratoma elements despite resolution of immature/malignant elements with administration of chemotherapy. Criteria for growing teratoma syndrome are: (i) normalization of elevated serum tumor markers; (ii) tumor growth during or after chemotherapy for nonseminomatous germ cell tumor; and (iii) the histologic presence of only mature teratoma at tumor resection [2,3]. Surgical resection is the only known cure for growing teratoma syndrome [4] but in the brain, complete resection may be impossible. Complications of growing teratoma syndrome usually arise from mass effect on adjacent structures [5]. In these instances, mature teratoma, although histologically benign, may be fatal [1].
CASE REPORT A 5-year-old presented with upward gaze paresis and headache. MRI scan showed a large mixed cystic and solid tumor arising from the pineal region, most consistent with germ cell tumor. Serum AFP was mildly elevated at 17 ng/ml. Serum beta HCG, CEA and CSF AFP, beta-HCG and CEA were normal. No other source of elevated AFP was identified. Biopsy showed mature CNS tissue and cytokeratin-positive squamous epithelium, consistent with mature teratoma. Serum and CSF tumor markers were repeated postoperatively and showed a serum AFP of 38 ng/ml and CSF AFP of 39 ng/ml thus the patient was diagnosed with intracranial nongerminomatous germ cell tumor. Cisplatin-based chemotherapy was initiated. MRI scan performed at the start of the third cycle of chemotherapy showed enlargement of the mixed cystic and solid mass concerning for tumor progression versus growing teratoma syndrome. Tumor markers were normal, confirming the diagnosis of intracranial growing teratoma syndrome. Chemotherapy was discontinued. Cytogenetic analysis of a posttreatment tumor biopsy C
showed 47, XY, þX, chromosome t(11;16) (q23;24) in all metaphase cells studied. Constitutional cytogenetics were normal. The patient underwent successive craniotomies in an attempt to debulk the tumor (Fig. 1) but unfortunately his tumor was not able to be completely resected and it continued to grow causing compression on critical areas and neurologic symptoms. The patient also developed extensive central venous sinus thrombosis (CVST) following multiple craniotomies. A single dose of interferon alpha-2b was administered but the patient developed respiratory distress requiring hospitalization thus interferon was discontinued. Based on the report by Vaughn et al. [6] showing stabilization of extracranial growing teratoma syndrome with PD0332991 (Palbociclib; Pfizer, New York, NY), a request was made to obtain permission for single patient use of PD0332991. As a condition of therapy, a previous biopsy specimen was tested for the presence of retinoblastoma protein (pRB) and was found to be positive, similar to the adult cases in the initial series. PD0332991 was initiated at a dose of 75 mg orally days 1–21 of each 28 day cycle. MRI showed stabilization of overall tumor size for approximately 3 months following initiation. Since that time, there has been ongoing stabilization of the enhancing, solidappearing areas which intraoperatively correlate to areas of solid, vascularized tissue. There has been slow progression of multiple nonenhancing, hypointense areas which appear cyst-like on MRI but intraoperatively contain mucoid, sebum-like substance. 1
Cancer and Blood Disorders, Children’s Hospitals and Clinics of Minnesota, Minneapolis, Minnesota; 2Neurosurgery, Children’s Hospitals and Clinics of Minnesota, Minneapolis, Minnesota; 3 Radiology, Children’s Hospitals and Clinics of Minnesota, Minneapolis, Minnesota; 4Hematology/Oncology, University of Pennsylvania, Philadelphia, Pennsylvania Conflict of interest: Nothing to declare. Palbociclib (PD033291) is an investigational compound and it is not approved for the treatment of this condition. Correspondence to: Kris Ann P. Schultz, Cancer and Blood Disorders, International OTST Registry, Children’s Hospital and Clinics of MN, 2530 Chicago Ave. S. CSC-175, Minneapolis, MN 55404. E-mail: [email protected]
Received 29 May 2014; Accepted 8 October 2014
2014 Wiley Periodicals, Inc. DOI 10.1002/pbc.25338 Published online 21 November 2014 in Wiley Online Library (wileyonlinelibrary.com).
Palbociclib for Intracranial Growing Teratoma
1073
Fig. 1. Radiographs showing: (A) Large pineal region germ cell tumor; (B) Increase in size of tumor despite normalization of tumor markers following initiation of chemotherapy and three successive craniotomies for partial debulking; (C) Growth of solid, enhancing components despite additional surgical debulking; (D) Slight decrease in size of tumor following initiation of PD0332991; (E) Stabilization of solid, enhancing components and growth of cystic components while on PD0332991; (F) Postcontrast MRI following thermoablation and 12 cycles of PD0332991.
Clinically, the patient has done well with significant improvement in his overall function and no further need for urgent surgical intervention for neurologic symptoms. Laser-interstitial thermal therapy has been performed twice and was well tolerated with reduction in tumor bulk following thermoablation. This stabilization was a change from his previous course during which he demonstrated tumor growth and clinical decline. Administration of the medication over 22 cycles has been well tolerated with uncomplicated neutropenia and fatigue as the only adverse events attributed to the medication. Height velocity is slowed although it remains unclear if this is due to medication, tumor or surgery. Recurrent CVST occurred, likely related to tumor and surgery. No grade III or IV side effects attributable to PD0332991 have been observed in this patient who remains alive and well 30 months after his diagnosis. Administration is ongoing and at least one additional laser thermoablation is planned.
DISCUSSION Oral PD0332991 is a selective reversible inhibitor of cyclindependent kinases (CDK) 4 and 6. Inhibition of CDK 4/6 blocks DNA synthesis by prohibiting progression of the cell cycle from G1 to S phase. Data from nonclinical studies indicate that PD0332991 may have cytoreductive as well as cytostatic effects on tumor cells. This oral kinase inhibitor has been utilized in adult trials including patients with advanced breast cancer [7], liposarcoma [8] and mantle cell lymphoma [9]. Mature teratomas express high levels of pRB. Cyclin dependent kinase 4/6 (CDK 4/6) stimulates cell growth by phophorylating pRB [6]. The use of PD0332991 in three adult patients with mature growing teratoma syndrome has been described by Vaughn et al. [6]. Pediatr Blood Cancer DOI 10.1002/pbc
Parrish et al. reported that the blood–brain barrier efflux pump may result in decreased brain penetration of PD0332991 in a murine model [10]. In our patient, however, it is possible that his blood–brain barrier was significantly disrupted by previous surgeries resulting improved distribution and increased efficacy. Also, the murine model may not be representative of the physiology of this pediatric germ cell tumor. In this report, we cannot rule out that the tumor may have stabilized without additional intervention; however, the history of growth and increased clinical symptoms until initiation of PD0332991 suggests the clinical course was stabilized by PD0332991. It is difficult to predict the growth of mature teratomas and thus difficult to determine the effect of an intervention on the natural history of growing teratoma. Following intervention, the patient’s clinical course and tumor appearance stabilized, however, in order to determine if this indicates a direct effect of the PD0332991, additional biologic, translational and clinical studies are needed. It is important to note that the biology of germ cell tumors is heterogeneous [11]. This pineal region tumor showed a gain of X which has been described in pineal germ cell tumor [12,13] and a chromosome t(11;16) translocation of uncertain clinical significance. The application of this case to children or adults with other brain tumors is unclear. Other strategies may be considered in the treatment of growing teratoma syndrome. These include interferon [14] and radiation. Radiation is a standard treatment of nongerminomatous germ cell tumors [15–17] but was not utilized in this case due to normalization of tumor markers and concern for the development of malignant transformation of the residual teratoma [18]. Radiation may be necessary in the future pending his clinical course.
1074
Schultz et al.
We report the use of PD0332991 in a pediatric patient with an intracranial teratoma. Importantly, PD0332991 appeared to cause stabilization of the vascularized, enhancing components of the tumor; however, the nonenhancing, hypointense areas continued to slowly progress and required additional treatment. The oral regimen was well tolerated. Although there was not complete radiographic stabilization, the partial stabilization allowed for a longer interval between surgical procedures and thus an overall more stable clinical course. Further investigation of the use of PD0332991in children with growing teratoma syndrome and potentially other refractory germ cell tumors may be warranted.
REFERENCES
8.
9.
10.
11.
12.
13. 14.
1. Kim CY, Choi JW, Lee JY, Kim SK, Wang KC, Park SH, Choe G, Ahn HS, Kim IH, Cho BK. Intracranial growing teratoma syndrome: Clinical characteristics andtreatment strategy. J Neurooncol 2011;101:109–115. 2. Logothetis CJ, Samuels ML, Trindade A, Johnson DE. The growing teratoma syndrome. Cancer 1982;50:1629–1635. 3. Lee DJ, Djaladat H, Tadros NN, Movassaghi M, Tejura T, Duddalwar V, Daneshmand S. Growing teratoma syndrome: Clinical and radiographic characteristics. Int J Urol 2014;21:905–908. 4. Denaro L, Pluchinotta F, Faggin R, Manara R, Calderone M, Viscardi E, Gardiman M, Rossetto M, Perilongo G, d’Avella D. What’s growing on? The growing teratoma syndrome. Acta Neurochir (Wien) 2010;152:1943–1946. 5. Byrd K, Stany MP, Herbold NC, Leath CA, 3rd, Hamilton CA. G rowing teratoma syndrome: Brief communication and algorithm for management. Aust N Z J Obstet Gynaecol 2013;53:318–321. 6. Vaughn DJ, Flaherty K, Lal P, Gallagher M, O’Dwyer P, Wilner K, Chen I, Schwartz G. Treatment of growing teratoma syndrome. N Engl J Med 2009;360:423–424. 7. Finn RS, Crown JP, Lang I, Boer K, Bondarenko IM, Kulyk SO, Ettl J, Patel T, Schmidt M, Shparyk Y, Thummala AR, Voytko NL, Breazna A, Kim ST, Randolph S, Slamon DJ. Results of a randomized phase 2 study of PD 0332991, a cyclin-dependent kinase (CDK) 4/6 inhibitor, in combination with Letrozole vs
Pediatr Blood Cancer DOI 10.1002/pbc
15.
16.
17.
18.
Letrozole alone for first-line treatment of ER+/HER2- advanced breast cancer (BC). Cancer Res 2012:72: Abstract nr S1–S6. Dickson MA, Tap WD, Keohan ML, D’Angelo SP, Gounder MM, Antonescu CR, Landa J, Qin LX, Rathbone DD, Condy MM, Ustoyev Y, Crago AM, Singer S, Schwartz GK. Phase II trial of the CDK4 inhibitor PD0332991 in patients with advanced CDK4-amplified well-differentiated or dedifferentiated liposarcoma. J Clin Oncol 2013;31:2024–2028. Leonard JP, LaCasce AS, Smith MR, Noy A, Chirieac LR, Rodig SJ, Yu JQ, Vallabhajosula S, Schoder H, English P, Neuberg DS, Martin P, Millenson MM, Ely SA, Courtney R, Shaik N, Wilner KD, Randolph S, Van den Abbeele AD, Chen-Kiang SY, Yap JT, Shapiro GI. Selective CDK4/6 inhibition with tumor responses by PD0332991 in patients with mantle cell lymphoma. Blood 2012;119:4597–4607. Parrish KE, Pokorny JL, Mittapalli RK, Bakken K, Sarkaria JN, Elmquist WF. BBB efflux pump activity limits brain 201 penetration of palbocicli (PD0332991) in glioblastoma. Mol Cancer Ther 2013;12:C81. Hersmus R, de Leeuw BH, Wolffenbuttel KP, Drop SL, Oosterhuis JW, Cools M, Looijenga LH. New insights into type II germ cell tumor pathogenesis based on studies of patients with various forms of disorders of sex development (DSD). Mol Cell Endocrinol 2008;291:1–10. Yu IT, Griffin CA, Phillips PC, Strauss LC, Perlman EJ. Numerical sex chromosomal abnormalities in pineal teratomas by cytogenetic analysis and fluorescence in situ hybridization. Lab Invest 1995;72:419– 423. Casalone R, Righi R, Granata P, Portentoso P, Minelli E, Meroni, Solero CL, Allegranza A. Cerebral germ cell tumor and XXY karyotype. Cancer Genet Cytogenet 1994;74:25–29. Ornadel D, Wilson A, Trask C, Ledermann J. Remission of recurrent mature teratoma with interferon therapy. JR Soc Med 1995;88:533P–534P. Khatua S, Dhall G, O’Neil S, Jubran R, Villablanca JG, Marachelian A, Nastia A, Lavey R, Olch AJ, Gonzalez I, Gilles F, Nelson M, Panigrahy A, McComb G, Krieger M, Fan J, Sposto R, Finlay JL. Treatment of primary CNS germinomatous germ cell tumors with chemotherapy prior to reduced dose whole ventricular and local boost irradiation. Pediatr Blood Cancer 2010;55:42–46. Calaminus G, Kortmann R, Worch J, Nicholson JC, Alapetite C, Garre ML, Patte C, Ricardi U, Saran F, Frappaz D. SIOP CNS GCT 96: Final report of outcome of a prospective, multinational nonrandomized trial for children and adults with intracranial germinoma, comparing craniospinal irradiation alone with chemotherapy followed by focal primary site irradiation for patients with localized disease. Neuro Oncol 2013;15:788–796. Kretschmar C, Kleinberg L, Greenberg M, Burger P, Holmes E, Wharam M. Pre-radiation chemotherapy with response-based radiation therapy in children with central nervous system germ cell tumors: A report from the Children’s Oncology Group. Pediatr Blood Cancer 2007;48:285–291. Glass T, Cochrane DD, Rassekh SR, Goddard K, Hukin J. Growing teratoma syndrome in intracranial nongerminomatous germ cell tumors (iNGGCTs): A risk for secondary malignant transformation-a report of two cases. Childs Nerv Syst 2014;30:953–959.
