J Neurooncol (2009) 92:65–71 DOI 10.1007/s11060-008-9736-9
CLINICAL STUDY - PATIENT STUDY
Long-term survival in primary CNS lymphoma treated by high-dose methotrexate monochemotherapy: role of STAT6 activation as prognostic determinant Seung-Ho Yang Æ Kun Soo Lee Æ Il Sup Kim Æ Jae Taek Hong Æ Jae Hoon Sung Æ Byung Chul Son Æ Sang Won Lee Æ Yong-Kil Hong
Received: 22 August 2008 / Accepted: 3 November 2008 / Published online: 22 November 2008 Ó Springer Science+Business Media, LLC. 2008
Abstract We report a single-center experience of 16 immunocompetent patients diagnosed with primary central nervous system lymphoma and treated with monochemotherapy with high-dose methotrexate (MTX) and deferred radiotherapy. MTX was given at a dose of 8.0 g/m2 for induction and at a dose of 3.5–8.0 g/m2 for maintenance. There were eight complete responses (CR), one partial response, one stable disease, and six patients whose tumors progressed in spite of the chemotherapy. At final follow-up, five of five CRs were alive and well without radiotherapy, with median follow-up of 26 months. Overall survival in eight non-CRs treated with the subsequent radiotherapy was 36 months. In the immunohistochemical study, STAT6 was positively expressed in 8 out of 13 cases. They included all non-CRs and two CRs. This observation suggests that STAT6 expression can be used as a prognostic determinant for MTX chemotherapy. Keywords Methotrexate Primary central nervous system lymphoma Chemotherapy Survival STAT6 Prognosis
S.-H. Yang I. S. Kim J. T. Hong J. H. Sung B. C. Son S. W. Lee Department of Neurosurgery, St. Vincent’s Hospital, The Catholic University of Korea, Suwon, South Korea K. S. Lee Y.-K. Hong (&) Department of Neurosurgery, Kangnam St. Mary’s Hospital, The Catholic University of Korea, 505 Banpo-dong, Seocho-gu, Seoul 137-701, South Korea e-mail:
[email protected]
Introduction Primary central nervous system lymphoma (PCNSL) is a rare non-Hodgkin’s lymphoma confined to the nervous system. The incidence of PCNSL has been increasing in Asian populations [1–3], which is not due to the high prevalence of human immunodeficiency virus in Asian countries, but is rather explained by increased use of improved diagnostic technology or environmental factors. The management of PCNSL is different from the standard treatment of both primary brain tumors and systemic nonHodgkin’s lymphoma. The first-generation chemotherapy regimens that are successfully used to treat systemic nonHodgkin’s lymphoma are ineffective for PCNSL, in part because of the blood–brain barrier [4]. Traditionally, PCNSL has been treated by means of chemotherapy or radiation or a combination of the two after biopsy confirmation of tumor histology. The addition of the methotrexate (MTX)-based chemotherapy has improved survival in patients with PCNSL. Studies of high-dose MTX chemotherapy in combination with other chemotherapeutic drugs, or as single-agent therapy, have demonstrated response rates of more than 50% in patients with newly diagnosed PCNSL [5–7]. Whole-brain radiation therapy results in high response rates but rapid relapse. Moreover, whole-brain radiation therapy is known to be associated with delayed neurotoxicity [8–10]. The recognition that neurotoxicity occurred in a significant proportion of PCNSL patients receiving whole-brain radiation therapy has led us to attempt to defer or eliminate this procedure. Recently, genetic studies began to elucidate features of the molecular pathogenesis of CNS lymphoma [11–13]. Ectopic expression of the B-cell growth factor interleukin (IL)-4 was demonstrated in PCNSL. IL-4 promoted lymphocyte survival and protected primary lymphoma from
123
66
apoptosis. The activation of the signal transducer and activator of transcription STAT6 was shown to be expressed by tumor cells and tumor endothelia in PCNSL, providing a significant role in the tumorigenesis. Even if the optimal protocol for PCNSL has not yet been defined, we evaluated the efficacy and safety of high-dose MTX monotherapy with deferred radiotherapy for the treatment of newly diagnosed PCNSL. Additionally, we investigated the expression of STAT6 by immunohistochemical staining to compare with response to MTX chemotherapy.
Materials and methods Inclusion criteria Patients with newly diagnosed PCNSL were eligible for enrollment in this study if a pathologic diagnosis had been established and all of the following criteria were met: age more than 18 years, Karnofsky performance status (KPS) C60, negative human immunodeficiency virus serology, creatinine clearance C60, and no evidence of lymphoma elsewhere in the body after computerized tomography scans of the chest, abdomen, and pelvis or gallium scan. Voluntary, informed, written consent was obtained from all patients. Treatment protocols Baseline prechemotherapy studies included neurological and physical examination, Mini-Mental State Examination, contrast-enhanced cranial magnetic resonance image (MRI), ophthalmologic examination including slit-lamp evaluation, and cytopathology of cerebrospinal fluid if lumbar puncture could be performed safely. A 24-h urine collection was obtained at baseline and before each cycle of chemotherapy cycle in order to calculate creatinine clearance. Patients were treated with MTX regimen with an induction and maintenance phase. Each MTX dose constituted a cycle. In the induction phase, patients received three cycles of MTX 8.0 g/m2 every 10 days and then the maintenance phase was begun. Three cycles of MTX 3.5 g/m2 were administered every 4 weeks, and thereafter MTX 3.5 g/m2 was administered once every 3 months. Leucovorin rescue (25 mg/m2, 4 times a day) was given intravenously 24 h after MTX administration and was continued until the daily plasma MTX level fell to\0.05 mmol/l. Adequate hydration was maintained throughout hospitalization, and urine was alkalinized to pH [7.0 by intravenous administration of NaHCO3. Each treatment cycle was standardized and required admission to hospital.
123
J Neurooncol (2009) 92:65–71
Three or six cycles of the maintenance chemotherapy was given to patients showing complete response to the induction chemotherapy. Whole-brain radiation therapy (5,040–5,440 cGy) was performed in cases where there was no objective response to high-dose MTX chemotherapy or a relapse of disease. Evaluation of response and toxicity Response was determined by contrast-enhanced MRI of the brain after the third and sixth cycles of chemotherapy. Complete response (CR) was defined as the total disappearance of all enhancing lesions on MRI of the brain in patients who were off corticosteroids. Partial response (PR) was defined as reduction of the enhancing tumor volume by more than 50%. Progression of disease (PD) was defined as increase in tumor volume of more than 25% or occurrence of new lesions, and stable disease (SD) was defined as any other situation [14]. Treatment failure was defined as progressive or stable disease, relapse after the initial response, death, or discontinuation of chemotherapy due to complications or because of personal or institutional decision. Acute toxicity was graded according to the National Cancer Institute toxicity criteria [15]. Immunohistochemistry Tumor specimens for 13 cases were retrieved from the Department of Hospital Pathology. For immunohistochemistry, the sections were deparaffinized, submerged in methanol containing 3% hydrogen peroxide activity, blocked, and immunostained using the avidin-biotin complex (ABC) method with diaminobenzidine as label (Vectastain ABC Elite Kit) according to the supplier’s instructions. The slides were then incubated with STAT6 (Thermo) antibodies at 1:100 dilution. For the negative control immunostaining anti-rabbit IgG whole molecule (Sigma-Aldrich) was used at 1:10,000 dilution. For the evaluation of STAT6 staining, cases were considered positive if at least 10% of the malignant cells demonstrated nuclear staining, according to a recent report [16]. Counterstaining was performed for 1 min with Mayer’s hematoxylin. Images were acquired using an Olympus BX41 microscope (Olympus, Tokyo, Japan) with a Camedia digital camera (JVC). All procedures were carried out at room temperature unless otherwise specified. Statistical analysis The objectives of this study were to evaluate the response rate, the safety of the chemotherapy regimen, progressionfree survival (PFS), and overall survival (OS). PFS was
J Neurooncol (2009) 92:65–71
67
Table 1 Patient characteristics (N = 16) Case
Sex
Age
Presenting symptom
1
M
22
Headache
2
F
40
3
M
46
4
F
5
KPS
Number of lesions
Surgery
Pathology
Cycles of chemo.
Response to HD-MTX
RT (cGy)
OS (month)
90
1
GTR
B-cell
8
CR
–
89?
Headache
100
2
GTR
B-cell
9
CR
–
44 (loss)
Headache
100
1
Bx
B-cell
6
CR
–
12?
48
Headache
100
2
Partial
T-cell
9
CR
–
24?
M
48
Dysarthria
80
1
Bx
B-cell
9
CR
–
20?
6
M
53
Headache
100
1
GTR
B-cell
9
CR
–
72 (loss)
7 8
F M
54 62
Headache Headache
90 90
1 1
GTR Partial
T-cell B-cell
8 6
CR CR
5400 –
50 68?
9
F
54
Headache
90
1
Bx
B-cell
6
PR
5040
48 (loss)
10
M
60
Headache
90
1
STR
B-cell
3
SD
5400
44
11
F
37
Headache
100
1
Bx
T-cell
3
PD
5040
6
12
F
42
Headache
90
1
Bx
B-cell
3
PD
5400
11?
13
M
50
Hemiparesis
14
F
63
Gait disturbance
15
F
64
16
F
70
80
1
Bx
B-cell
3
PD
5400
15
100
1
STR
B-cell
6
PD
5440
36
Headache
90
1
Bx
B-cell
3
PD
5040
13?
Headache
90
1
Bx
B-cell
3
PD
–
6
KPS Karnofsky performance status, Chemo chemotherapy, HD-MTX high-dose methotrexate, RT radiation therapy, OS overall survival, GTR gross total resection, CR complete response, Bx biopsy, PR partial response, STR subtotal resection, SD stable disease, PD progression of disease ?
Indicates that patient is still alive
measured from start of MTX administration to tumor progression or to withdrawal from the study. OS was calculated from date of histological diagnosis to date of death or last date of follow-up. Relapse or progression was defined as tumor growth or regrowth at any site within or outside of the central nervous system. Kaplan–Meier method was used to estimate OS and PFS using SPSS software (version 11.0, Chicago, IL).
Results Characteristics of patients From 2000 to 2005, 16 immunocompetent patients (7 men and 9 women) were treated primarily with high-dose MTX chemotherapy according to protocol guidelines. Median age of the patients was 51.5 years (range 22–70 years). Pretreatment Karnofsky performance status (KPS) scores ranged from 80 to 100 (median 90). Fourteen patients had a lesion in the supratentorial region and two patients had a solitary lesion in the cerebellar hemisphere. Median number of treatment cycles was 6 (range 3–9 cycles) and median follow-up period was 32 months (range 7–90 months). Thirteen patients were diagnosed with diffuse, large B-cell lymphoma and three patients (18.8%) were diagnosed with T-cell lymphoma according to the World
Health Organization (WHO) classification [17]. The main clinical features of the patients are summarized in Table 1. Response and survival This cohort study showed eight CRs (50%), one PR (6.7%), one SD (6.7%) and six PDs (37.5%). Five of the eight complete responders (CR group) are alive and well without radiotherapy during median follow-up of 26 months. One patient (case 7) had a relapse 25 months after the initial chemotherapy, but this patient was in a second complete remission after treatment with adjuvant radiotherapy. The patients in the non-CR group, including those with PR, SD, and PD, were immediately treated with the adjuvant radiotherapy during or after the chemotherapy regimen. One patient (case 11) developed leptomeningeal seeding during the radiotherapy. One patient (case 13) achieved complete radiographic response to the radiotherapy (5,400 cGy) but recurred 8 weeks after the completion of the radiotherapy. One patient (case 14) showed no response to the radiotherapy and died due to tumor progression. One patient (case 16) had rapid progression of tumor and did not receive the radiotherapy. In the non-CR group, median PFS to the chemotherapy was 8 weeks. Median OS of all patients was 50 months. Median survival of the patients in the CR group has not yet been determined and median OS of the non-CR group was 36 months (P-value 0.005) (Fig. 1).
123
68
J Neurooncol (2009) 92:65–71
and two CRs (cases 4 and 5) to high-dose MTX chemotherapy. STAT6 immunoreactivity was not shown in five CRs (cases 1, 2, 3, 6, and 7). Tumors that contained foci in which dense populations of lymphoma cells scored positive for STAT6 expression were associated with short overall survival in comparison with tumors that exhibited absent STAT6 (P-value 0.037) (Fig. 3).
Discussion
Fig. 1 Cumulative overall survival rate according to Kaplan–Meier : complete responders, - - - - - - : all survival plots. ( : non-complete responders) patients,
Toxicity Toxicity was modest after 94 cycles of hospital-based MTX chemotherapy. Myelosuppression developed mainly during the induction cycle. Most of the nonhematological toxicity resulted in gastrointestinal problem, and these patients were treated with conservative care and did not drop out of the study. Transient nephrotoxicity developed in one patient. Chemotherapy-related chest tightness developed in one patient. No mortality related to the chemoradiotherapy occurred during the treatment period. Treatment-related toxicities are outlined in Table 2. Immunohistochemical findings We characterized STAT6 activation in an independent set of 13 cases (7 CRs and 6 non-CRs) with immunohistochemical staining (Fig. 2). STAT6 immunoreactivity was positive in eight cases. They included all non-CR patients Table 2 Toxicity according to National Cancer Institute toxicity criteria Grade 1 Neutropenia
2
Thrombocytopenia
2
Anemia Hepatitis
Grade 3
1
Renal Nausea
Grade 2
1 3
2
1
Stomatitis Other
123
Chest tightness
Grade 4
Approximately 10 years ago, several investigators [18–22] started to treat patients with newly diagnosed PCNSL with MTX chemotherapy alone and deferred whole-brain radiation therapy. Following these protocols, patients newly diagnosed with PCNSL have been treated with high-dose MTX monotherapy in our hospital. We achieved eight CRs (50%) in 16 patients treated with the high-dose MTX regimen. The most gratifying aspect of this therapy was the establishment of durable CRs with preserved performance status. Median survival of the patients in the CR group has not yet been determined because five out of the eight patients who had CR to the chemotherapy are still alive. Therefore, this study raises the questions of which factor is associated with good response to the MTX chemotherapy, and what are the differences between the patients in the CR group and those in the non-CR group. An international multicenter retrospective study of 378 immunocompetent patients with PCNSL treated by primary chemotherapy containing high-dose MTX concluded that age, performance status, lactate dehydrogenase serum level, protein concentration in cerebrospinal fluid, and involvement of deep structures of the brain were independent predictors of survival [23]. Several other potential prognostic parameters such as pathologic type [24], duration of symptoms, subtentorial localization, and bilateral brain involvement [25, 26] were proposed but failed to be confirmed in subsequent studies. In this study, there was no statistical difference between the CR and non-CR groups in terms of age, initial performance status, tumor location and number, type of pathology or extent of resection. We searched for possible predictors of response to highdose MTX chemotherapy in the literature. It is revealed that IL-4 is highly expressed in angiotrophic tumor cells of PCNSL, and increased expression of STAT6 in tumor cells and endothelia predict early progression and short survival in patients treated with high-dose MTX chemotherapy [27]. Consistent with the result, immunoreactivity to STAT6 was expressed in all patients with non-CR to high-dose MTX chemotherapy. STAT6 immunohistochemical study of seven CRs included negative expression in five cases and weak positive expression in two. In a variety of human cancers (breast, leukemia, lymphomas, prostate, and head
J Neurooncol (2009) 92:65–71
Fig. 2 STAT6 immunohistochemical staining of primary central nervous system lymphoma. a Strong expression in a patient (case 13) with tumor progression following high-dose MTX chemotherapy
Fig. 3 Cumulative overall survival rate according to Kaplan–Meier : absent STAT6 expression, - - - - - - : survival plots. ( positive STAT6 expression)
and neck) constitutive activation of STAT signaling has been observed [28, 29]. STAT6 overexpression might produce a wide array of cytokines and stimulate the epithelia nearby, which may cause a remodeled extracellular matrix (ECM) with the help of matrix metalloproteinases
69
(9400). b Absent expression in a patient (case 3) with complete response to MTX chemotherapy (9400). c Specific pure rabbit IgG was used as a negative control (9400)
(MMPs) and a spectrum of growth factors. The ECM regulates important physiological functions associated with cancers such as tissue differentiation, proliferation, and homeostasis [30]. Similarly, it is suggested that STAT6 is a survival factor in prostate cancer and regulates the genetic transcriptional program that is responsible for prostate cancer progression [31]. Two studies evaluated the efficacy of high-dose MTX alone (8 g/m2) for newly diagnosed patients, with wholebrain radiation therapy administered only at disease recurrence using a protocol similar to the protocol used in the present study. The new approaches to brain tumor therapy CNS consortium (NABTT) 96-07 trial reported median PFS of 13 months, and median OS had not been reached at 23? months with a radiographic response (74%) and modest toxicity [32]. On the other hand, the neurooncology working group of the German Cancer Society (NOA)-03 trial concluded that high-dose MTX with deferred radiotherapy had only modest efficacy and was associated with significant neurotoxicity in long-term surviving patients [33]. Late neurotoxic sequelae are more frequent and more severe in patients treated with additional radiotherapy [34]. Therefore, achievement of better survival with less neurotoxicity may depend on initial response to high-dose MTX chemotherapy in our treatment protocol.
123
70
The non-CR group was treated by subsequent wholebrain radiation therapy (WBRT), with median overall survival of 36 months. Five of the patients in the non-CR group (71%) showed radiographic response (CR?PR?SD) to the radiotherapy with median duration of 8 weeks. Practically, it is important to determine which patients will not respond to HD-MTX and to offer second-line therapy, such as WBRT, reinduction with MTX [35] or temozolomide chemotherapy [36], as soon as possible. However, the appropriate time for determining which patients will be nonresponders, such as after the induction phase or the maintenance phase, remains uncertain. It is also questionable how many cycle of chemotherapy should be administered to complete responders. Even though the number of patients studied was small, our study showed favorable outcomes in terms of survival and toxicity, especially in patients with CR to the highdose MTX chemotherapy. We suggest that STAT6 expression pattern can be a useful predictor of response to high-dose MTX chemotherapy. Acknowledgement The authors would like to thank Professor Tali Siegal for reviewing the manuscript.
References 1. Tseng MY, Tu YK, Shun CT (1998) Primary central nervous system lymphoma: a retrospective study. J Clin Neurosci 5:409– 412. doi:10.1016/S0967-5868(98)90273-9 2. Shibamoto Y, Tsuchida E, Seki K, Oya N, Hasegawa M, Toda Y, Takemoto M, Sumi M, Hiratsuka J, Oguchi M, Hosono M, Yasuda S, Sougawa M, Kakutoh Y, Hayabuchi N (2004) Primary central nervous system lymphoma in Japan 1995–1999: changes from the preceding 10 years. J Cancer Res Clin Oncol 130:351– 356. doi:10.1007/s00432-004-0547-x 3. Quek R, Ty A, Lim ST, See S, Wong MC, Yap SP, Sng I, Hee SW, Tao M (2006) Primary central nervous system lymphoma in an Asian population: a 15-year experience. Onkologie 29:455– 459. doi:10.1159/000095342 4. Schultz C, Scott C, Sherman W, Donahue B, Fields J, Murray K, Fisher B, Abrams R, Meis-Kindblom J (1996) Preirradiation chemotherapy with cyclophosphamide, doxorubicin, vincristine, and dexamethasone for primary CNS lymphoma: initial report of radiation therapy oncology group protocol 88-06. J Clin Oncol 14:556–564 5. Guha-Thakurta N, Damek D, Pollack C, Hochberg FH (1999) Intravenous methotrexate as initial treatment for primary central nervous system lymphoma: response to therapy and quality of life of patients. J Neurooncol 43:259–268. doi:10.1023/A:1006210703827 6. McAllister LD, Doolittle ND, Guastadisegni PE, Kraemer DF, Lacy CA, Crossen JR, Neuwelt EA (2000) Cognitive outcomes and long-term follow-up results after enhanced chemotherapy delivery for primary central nervous system lymphoma. Neurosurgery 46:51–61. doi:10.1097/00006123-200001000-00010 7. O’Brien P, Roos D, Pratt G, Liew K, Barton M, Poulsen M, Olver I, Trotter G (2000) Phase II multicenter study of brief singleagent methotrexate followed by irradiation in primary CNS lymphoma. J Clin Oncol 18:519–526
123
J Neurooncol (2009) 92:65–71 8. Abrey LE, Yahalom J, De Angelis LM (1997) Relapse and late neurotoxicity in primary central nervous system lymphoma. Neurology 48:A18 9. Siobhan NG, Rosenthal MA, Ashley D, Cher L (2000) High dose methotrexate for primary CNS lymphoma in the elderly. Neuro Oncol 2:40–44. doi:10.1215/15228517-2-1-40 10. Bessell EM, Graus F, Lopez-Guillermo A, Lewis SA, Villa S, Verger E, Petit J (2001) CHOP/BVAM regimen plus radiotherapy in patients with primary CNS non Hodgkin’s lymphoma. Int J Radiat Oncol Biol Phys 50:457–464. doi:10.1016/S0360-3016 (01)01451-1 11. Lu X, Nechushtan H, Ding F, Rosado MF, Singal R, Alizadeh AA, Lossos IS (2005) Distinct IL-4-induced gene expression, proliferation, and intracellular signaling in germinal center B-cell-like and activated B-cell-like diffuse large-cell lymphomas. Blood 105:2924–2932. doi:10.1182/blood-2004-10-3820 12. Bruns HA, Kaplan MH (2006) The role of constitutively active Stat6 in leukemia and lymphoma. Crit Rev Oncol Hematol 57:245–253. doi:10.1016/j.critrevonc.2005.08.005 13. Carey GB, Semenova E, Qi X, Keegan AD (2007) IL-4 protects the B-cell lymphoma cell line CH31 from anti-IgM-induced growth arrest and apoptosis: contributing of the PI-3 kinase/AKT pathway. Cell Res 17:942–955. doi:10.1038/sj.cr.2007.90 14. Macdonald DR, Cascino TL, Schold SC Jr, Cairncross JG (1990) Response criteria for phase II studies of supratentorial glioma. J Clin Oncol 8:1277–1280 15. Miller AB, Hoogstraten B, Staquet M, Winkler A (1981) Reporting results of cancer treatment. Cancer 47:207–214. doi:10.1002/ 1097-0142(19810101)47:1\207::AID-CNCR2820470134[3.0. CO;2-6 16. Skinnider BF, Elia AJ, Gascoyne RD, Patterson B, Trumper L, Kapp U, Mak TW (2002) Signal transducer and activator of transcription 6 is frequently activated in Hodgkin and ReedSternberg cells of Hodgkin lymphoma. Blood 15:618–626. doi: 10.1182/blood.V99.2.618 17. Gatter KC, Warnke RA (2002) Diffuse large cell lymphoma. In: Jaffe ES, Harris NL, Stein H, Vardiman JV (eds) Pathology and genetics of tumors of haematopoietic and lymphoid tissues. IARC, Lyon, pp 171–174 18. Neuwelt EA, Goldman DL, Dahlborg SA, Crossen J, Ramsey F, Roman-Goldstein S, Braziel R, Dana B (1991) Primary CNS lymphoma treated with osmotic blood-brain barrier disruption: prolonged survival and preservation of cognitive function. J Clin Oncol 9:1580–1590 19. Cher L, Glass J, Harsh GR, Hochberg FH (1996) Therapy of primary central nervous system lymphoma with methotrexatebased chemotherapy and deferred radiotherapy: preliminary results. Neurology 46:1757–1759 20. Freilich RJ, Delattre JY, Monjour A, De Angelis LM (1996) Chemotherapy without radiation therapy as initial treatment for primary CNS lymphoma in older patients. Neurology 46:435–439 21. Hoang-Xuan K, Chinot O, Frenay M, Taillandier L, Hildebrand J, Monjour A, van den Bent M, Sahmoud T, Poisson M, Delattre JY (1997) Chemotherapy alone as initial treatment of primary central nervous system. Neurology 48:A17 22. Sherman W, Balmaceda C, Nichols G, Mears G, Antman K (1997) Feasibility of 3 g/m2 of intravenous methotrexate for primary central nervous system lymphoma. Neurology 48:A17–A18 23. Ferreri AJ, Blay JY, Reni M, Pasini F, Spina M, Ambrosetti A, Calderoni A, Rossi A, Vavassori V, Conconi A, Devizzi L, Berger F, Ponzoni M, Borisch B, Tinquely M, Cerati M, Milani M, Orvieto E, Sanchez J, Chevreau C, Dell’Oro S, Zucca E, Cavalli F (2003) Prognostic scoring system for primary CNS lymphoma: the International Extranodal Lymphoma Study Group Experience. J Clin Oncol 21:266–272. doi:10.1200/JCO.2003.09.139
J Neurooncol (2009) 92:65–71 24. Helle TL, Britt RH, Golby TV (1984) Primary lymphoma of the central nervous system: clinicopathological study of experience at Stanford. J Neurosurg 60:94–103 25. Pollack IF, Lunsford LD, Flickinger JC, Dameshek HL (1989) Prognostic factors in the diagnosis and treatment of primary central nervous system lymphoma. Cancer 63:939–947. doi:10.1002/10970142(19890301)63:5\939::AID-CNCR2820630526[3.0.CO;2-V 26. Michalski JM, Garcia DM, Kase E, Griqsby PW, Simpson JR (1990) Primary central nervous system lymphoma: analysis of prognostic variables and patterns of treatment failure. Radiology 176:855–860 27. Rubenstein JL, Fridlyand J, Shen A, Aldape K, Ginzinger D, Batchelor T, Treseler P, Berger M, McDermott M, Prados M, Karch J, Okada C, Hyun W, Parikh S, Haqq C, Shuman M (2006) Gene expression and angiotropism in primary CNS lymphoma. Blood 107:3716–3723. doi:10.1182/blood-2005-03-0897 28. Buettner R, Mora LB, Jove R (2002) Activated STAT signaling in human tumors provides novel molecular targets for therapeutic intervention. Clin Cancer Res 8:945–954 29. Gao L, Zhang L, Hu J, Li F, Shao Y, Zhao D, Kalvakolanu DV, Kopecko DJ, Zhao X, Xu DQ (2005) Down-regulation of signal transducer and activator of transcription 3 expression using vector-based small interfering RNAs suppresses growth of human prostate tumor in vivo. Clin Cancer Res 11:6333–6341. doi: 10.1158/1078-0432.CCR-05-0148 30. Bissell MJ, Radisky DC, Rizki A, Weaver VM, Petersen OW (2002) The organizing principle: microenvironmental influences
71
31.
32.
33.
34.
35.
36.
in the normal and malignant breast. Differentiation 70:537–546. doi:10.1046/j.1432-0436.2002.700907.x Das S, Roth CP, Wasson LM, Vishwanatha JK (2007) Signal transducer and activator of transcription-6 (STAT6) is a constitutively expressed survival factor in human prostate cancer. Prostate 67:1550–1564. doi:10.1002/pros.20640 Batchelor T, Carson K, O’Neill A, Grossman SA, Alavi J, New P, Hochberg F, Priet R (2003) Treatment of primary CNS lymphoma with methotrexate and deferred radiotherapy: a report of NABTT 96-07. J Clin Oncol 21:1044–1049. doi:10.1200/JCO. 2003.03.036 Herrlinger U, Kuker W, Uhl M, Blaicher H, Karnath H, Kanz L, Bamberg M, Weller M (2005) NOA-03 trial of high-dose methotrexate in primary central nervous system lymphoma: final report. Ann Neurol 57:843–847. doi:10.1002/ana.20495 Harder H, Holtel H, Bromberg JE (2004) Cognitive status and quality of life after treatment for primary CNS lymphoma. Neurology 62:544–547 Chon B, Hochberg F, Loeffler J, Batchelor T (2001) Methotrexate reinduction in patients with relapsed primary central nervous system lymphoma. Neuro Oncol 3:356 Reni M, Mason W, Zaja F, Franceschi E, Bernardi D, Dell’Oro S, Stelitano C, Candela M, Abbadessa A, Pace A, Bordonaro R, Latte G, Villa E, Ferreri AJ (2004) Salvage chemotherapy with temozolomide in primary CNS lymphomas: preliminary results of a phase II trial. Eur J Cancer 40:1682–1688. doi:10.1016/j.ejca. 2004.03.008
123
