Prognostic significance of S-phase kinase-associated protein 2 and p27kip1 in patients with diffuse large B-cell lymphoma: effects of rituximab.
BACKGROUND
The F-box protein S-phase kinase-associated protein 2 (Skp2) positively regulates the G1-S transition by promoting degradation of the cyclin-dependent kinase inhibitor p27(kip1) (p27). Recent evidence has indicated an oncogenic role of Skp2 in not only carcinogenesis but also lymphomagenesis.


METHODS
Clinicopathologic features and immunohistochemical expression of Skp2 and p27 were studied retrospectively in 671 patients treated with cyclophosphamide, vincristine, doxorubicin and prednisolone (CHOP) or cyclophosphamide, vincristine, doxorubicin and prednisolone plus rituximab (R-CHOP). The median follow-up periods were 43.2 months in the CHOP group (n = 425) and 24.0 months in the R-CHOP group (n = 246).


RESULTS
High Skp2 or low p27 expression correlated significantly with poor overall survival (OS) and progression-free survival (P < 0.001) in both treatment groups. The prognostic value of Skp2 or p27 expression was independent of the parameters included in the International Prognostic Index by multivariate analysis. Patients with high Skp2 expression in combination with low p27 expression showed the worst survival.


CONCLUSIONS
Addition of rituximab to the CHOP regimen did not provide a beneficial outcome to patients with diffuse large B-cell lymphoma with high Skp2 expression and low p27 expression. Skp2 and p27 may be useful prognostic markers in the rituximab era.
Seki
R
R
Division of Hematology and Oncology, Department of Medicine.
Ohshima
K
K
Department of Pathology, Research Center for Innovative Cancer Therapy, Kurume University School of Medicine, Fukuoka.
Fujisaki
T
T
Department of Internal Medicine, Matsuyama Red Cross Hospital, Ehime.
Uike
N
N
Department of Hematology, National Kyushu Cancer Center, Fukuoka.
Kawano
F
F
Department of Internal Medicine, National Hospital Organization Kumamoto Medical Center, Kumamoto.
Gondo
H
H
Department of Internal Medicine, Saga Prefectural Hospital, Koseikan, Saga.
Makino
S
S
Department of Internal Medicine, Miyazaki Prefectural Hospita, Miyazakil.
Eto
T
T
Department of Hematology, Hamanomachi Hospital, Fukuoka.
Moriuchi
Y
Y
Department of Hematology, Sasebo City General Hospital, Nagasaki.
Taguchi
F
F
Department of Hematology, Iizuka Hospital.
Kamimura
T
T
Department of Hematology, Harasanshin General Hospital, Fukuoka.
Tsuda
H
H
Division of Hematology and Oncology, Kumamoto City Hospital, Kumamoto.
Shimoda
K
K
Department of Internal Medicine, Gastroenterology and Hematology, Faculty of Medicine, Miyazaki University, Miyazaki, Japan.
Okamura
T
T
Division of Hematology and Oncology, Department of Medicine. Electronic address: okamura@med.kurume-u.ac.jp.
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000627:therapeutic use*; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols; D014408:Biomarkers, Tumor / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D003520:Cyclophosphamide; D004317:Doxorubicin; D005260:Female; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000175:diagnosis* / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D008297:Male; D008875:Middle Aged; D011241:Prednisone; D011379:Prognosis; D012189:Retrospective Studies; D000069283:Rituximab; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism*; D016019:Survival Analysis; D014750:Vincristine; D055815:Young Adult
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D044786:S-Phase Kinase-Associated Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone