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Thomas E Witzig,
Gregory A Wiseman,
Matthew J Maurer,
Thomas M Habermann,
Ivana N M Micallef,
Grzegorz S Nowakowski,
Stephen M Ansell,
Joseph P Colgan,
David J Inwards,
Luis F Porrata,
Brian K Link, Clive S Zent,
Patrick B Johnston,
Tait D Shanafelt,
Cristine Allmer,
Yan W Asmann,
Mamta Gupta,
Zuhair K Ballas,
Brian J Smith,
George J Weiner
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ABSTRACT: Radioimmunotherapy (RIT) for relapsed indolent non-Hodgkin lymphoma produces overall response rates (ORR) of 80% with mostly partial remissions. Synthetic CpG oligonucleotides change the phenotype of malignant B-cells, are immunostimulatory, and can produce responses when injected intratumorally and combined with conventional radiation. In this phase I trial we tested systemic administration of both CpG and RIT. Eligible patients had biopsy-proven previously treated CD20+ B-cell NHL and met criteria for RIT. Patients received rituximab 250 mg/m(2) days 1,8, and 15; (111) In-ibritumomab tiuxetan days 1, 8; CpG 7909 days 6, 13, 20, 27; and 0.4 mCi/kg of (90) Y- ibritumomab tiuxetan day 15. The doses of CpG 7909 tested were 0.08, 0.16, 0.32 (six patients each) and 0.48 mg/kg (12 patients) IV over 2 hours without dose limiting toxicity. The ORR was 93% (28/30) with 63% (19/30) complete remission (CR); median progression free survival of 42.7 months (95% CI 18-NR); and median duration of response (DR) of 35 months (4.6-76+). Correlative studies demonstrated a decrease in IL10 and TNFα, and an increase in IL1β, in response to therapy. CpG 7909 at a dose of 0.48 mg/kg is safe with standard RIT and produces a high CR rate and long DR; these results warrant confirmation.
American Journal of Hematology 04/2013; · 4.67 Impact Factor
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Tait D Shanafelt,
Alan G Ramsay, Clive S Zent,
Jose F Leis,
Han W Tun,
Timothy G Call,
Betsy Laplant,
Deborah Bowen,
Adam Pettinger,
Diane F Jelinek,
Curtis A Hanson,
Neil E Kay
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ABSTRACT: Key points Lenalidomide consolidation repairs T-cell immunologic synapses in CLL patientsLenalidomide consolidation improved the quality of response in CLL patients treated with chemoimmunotherapy.
Blood 03/2013; · 9.90 Impact Factor
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ABSTRACT: Compelling evidence indicates Type I CD20 immunotherapeutic mAbs promote targeted tumor cell elimination exclusively via immune effector functions, which can be exhausted/saturated. mAb dosing paradigms should therefore take into account the capacity of these cytotoxic mechanisms, leading to the conclusion that lower doses, given frequently, may be far more effective.
Oncoimmunology. 09/2012; 1(6):959-961.
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New England Journal of Medicine 08/2012; 367(9):876-7; author reply 878. · 53.30 Impact Factor
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ABSTRACT: Thirty-three previously untreated patients with high-risk chronic lymphocytic leukemia (CLL) were treated before meeting standard criteria with alemtuzumab and rituximab. Granulocyte macrophage colony stimulating factor (GM-CSF) was added to the regimen to determine whether it would improve treatment efficacy without increasing toxicity. High risk was defined as at least one of the following: 17p13-; 11q22.3-; unmutated IGHV (or use of VH3-21) together with elevated expression of ZAP-70 and/or CD38. Treatment was subcutaneous GM-CSF 250 μg Monday-Wednesday-Friday for 6 weeks from day 1, subcutaneous alemtuzumab 3 mg-10 mg-30 mg from day 3 and then 30 mg Monday-Wednesday-Friday for 4 weeks, and intravenous rituximab (375 mg/m(2)/week) for 4 weeks from day 8. Patients received standard supportive care and were monitored weekly for cytomegalovirus (CMV) reactivation. Using standard criteria, 31 (94%) patients responded to treatment, with nine (27%) complete responses (one with persistent cytopenia) and nine (27%) nodular partial responses. Median progression-free survival was 13.0 months and time to next treatment was 33.5 months. No patient died during treatment, seven (21%) had grade 3-4 toxicities attributable to treatment, and 10 (30%) had CMV viremia. Addition of GM-CSF to therapy with alemtuzumab and rituximab decreased treatment efficacy and increased the rate of CMV reactivation compared to a historical control.
Leukemia & lymphoma 08/2012; · 2.40 Impact Factor
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Tait D Shanafelt,
Timothy G Call, Clive S Zent,
Jose F Leis,
Betsy Laplant,
Deborah A Bowen,
Michelle Roos,
Kristina Laumann,
Asish K Ghosh,
Connie Lesnick,
Mao-Jung Lee,
Chung S Yang,
Diane F Jelinek,
Charles Erlichman,
Neil E Kay
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ABSTRACT: BACKGROUND: The objective of the current study was to follow up the results of phase 1 testing by evaluating the clinical efficacy of the green tea extract Polyphenon E for patients with early stage chronic lymphocytic leukemia (CLL). METHODS: Previously untreated patients with asymptomatic, Rai stage 0 to II CLL and an absolute lymphocyte count (ALC) ≥ 10 × 10(9) /L were eligible for this phase 2 trial. Polyphenon E with a standardized dose of epigallocatechin gallate (EGCG) (2000 mg per dose) was administered twice daily. RESULTS: A total of 42 patients received Polyphenon E at a dose of 2000 mg twice daily for up to 6 months. Of these patients, 29 (69%) had Rai stage I to II disease. Patients received a median of 6 cycles of treatment (range, 1 cycle-6 cycles). The most common grade 3 side effects (according to National Cancer Institute Common Terminology Criteria for Adverse Events) were transaminitis (1 patient), abdominal pain (1 patient), and fatigue (1 patient). Clinical activity was observed, with 13 patients (31%) experiencing a sustained reduction of ≥ 20% in the ALC and 20 of 29 patients (69%) with palpable adenopathy experiencing at least a 50% reduction in the sum of the products of all lymph node areas. EGCG plasma levels after 1 month of therapy were found to be correlated with reductions in lymphadenopathy (correlation co-efficient, 0.44; P = .02). Overall, 29 patients (69%) fulfilled the criteria for a biologic response with either a sustained decline ≥ 20% in the ALC and/or a reduction ≥ 30% in the sum of the products of all lymph node areas at some point during the 6 months of active treatment. CONCLUSIONS: Daily oral EGCG in the Polyphenon E preparation was well tolerated by patients with CLL in this phase 2 trial. Durable declines in the ALC and/or lymphadenopathy were observed in the majority of patients. Cancer 2012. © 2012 American Cancer Society.
Cancer 07/2012; · 4.77 Impact Factor
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Bridget Charbonneau,
Matthew J Maurer,
Zachary S Fredericksen, Clive S Zent,
Brian K Link,
Anne J Novak,
Stephen M Ansell,
George J Weiner,
Alice H Wang,
Thomas E Witzig,
Ahmet Dogan,
Susan L Slager,
Thomas M Habermann,
James R Cerhan
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ABSTRACT: The complement pathway plays a central role in innate immunity, and also functions as a regulator of the overall immune response. We evaluated whether polymorphisms in complement genes are associated with event-free survival (EFS) in follicular lymphoma (FL) and diffuse large B-cell (DLBCL) lymphoma. We genotyped 167 single nucleotide polymorphisms (SNPs) from 30 complement pathway genes in a prospective cohort study of newly diagnosed FL (N = 107) and DLBCL (N = 82) patients enrolled at the Mayo Clinic from 2002 to 2005. Cox regression was used to estimate hazard ratios (HRs) for individual SNPs with EFS, adjusting for FLIPI or IPI and treatment. For gene-level analyses, we used a principal components based gene-level test. In gene-level analyses for FL EFS, CFH (P = 0.009), CD55 (P = 0.006), CFHR5 (P = 0.01), C9 (P = 0.02), CFHR1 (P = 0.03), and CD46 (P = 0.03) were significant at P < 0.05, and these genes remained noteworthy after accounting for multiple testing (q < 0.15). SNPs in CFH, CFHR1, and CFHR5 showed stronger associations among patients receiving any rituximab, while SNPs from CD55 and CD46 showed stronger associations among patients who were observed. For DLBCL, only CLU (P = 0.001) and C7 (P = 0.03) were associated with EFS, but did not remain noteworthy after accounting for multiple testing (q>0.15). Genes from the regulators of complement activation (CFH, CD55, CFHR1, CFHR5, CD46) at 1q32-q32.1, along with C9, were associated with FL EFS after adjusting for clinical variables, and if replicated, these findings add further support for the role of host innate immunity in FL prognosis.
American Journal of Hematology 05/2012; 87(9):880-5. · 4.67 Impact Factor
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ABSTRACT: Abstract Complement dependent cytotoxicity (CDC) is an important mechanism of action for monoclonal antibodies (mAbs) used in the treatment of chronic lymphocytic leukemia (CLL). We hypothesized that alemtuzumab (ALM) mediated CDC would be increased by the addition of ofatumumab (OFA). CLL cells from 21 previously untreated patients with progressive disease were tested in vitro for mAb binding, complement activation and CDC. The subpopulation of CDC resistant CLL cells was examined for levels of C3b and C5b-9 binding, and expression of complement regulatory proteins. OFA significantly increased complement activation and CDC in ALM-treated CLL cells, suggesting that combining ALM and OFA could improve clinical outcome in patients with CLL. Approximately 10% of CLL cells were resistant to CDC because of lower levels of complement activation or decreased cytotoxicity of activated complement. Improvement of clinical responses will require determining the mechanisms of CDC resistance and developing methods to overcome this problem.
Leukemia & lymphoma 04/2012; 53(11):2218-27. · 2.40 Impact Factor
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British Journal of Haematology 11/2011; 156(5):674-6. · 4.94 Impact Factor
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Tait D Shanafelt,
Neil E Kay,
Kari G Rabe,
David J Inwards, Clive S Zent,
Jose F Leis,
Susan M Schwager,
Carrie A Thompson,
Deborah A Bowen,
Thomas E Witzig,
Susan L Slager,
Timothy G Call
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ABSTRACT: The impact of physicians' disease-specific expertise on patient outcome is unknown. Although previous studies suggest a survival advantage for cancer patients cared for at high-volume centers, these observations may simply reflect referral bias or better access to advanced technologies, clinical trials, and multidisciplinary support at large centers.
We evaluated time to first treatment (TTFT) and overall survival (OS) of patients with newly diagnosed chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) at a single academic center based on whether they were cared for by a hematologist/oncologist who subspecializes in CLL (CLL hematologist) or a hematologist/oncologist with expertise in other areas (non-CLL hematologist).
Among 1309 newly diagnosed patients with CLL cared for between 1999 and 2009, 773(59%) were cared for by CLL hematologists and 536 were cared for by non-CLL hematologists. Among early-stage patients (Rai 0-I), median TTFT (9.2 vs 6.1 years; P < .001) and OS (10.5 years vs 8.8 years; P < .001) were longer for patients cared for by CLL hematologists. For all patients, OS was superior for patients cared for by CLL hematologists (10.5 years vs 8.4 years; P = .001). Physician's disease-specific expertise remained an independent predictor of OS after adjusting for age, sex, stage, and lymphocyte count at diagnosis. Patients seen by a CLL hematologist were also more likely to participate in clinical trials (48% vs 16%; P < .001).
Physician disease-specific expertise appears to influence outcome in patients with CLL. To the greatest extent possible, patients should be cared for by a hematologist/oncologist expert in the care of their specific malignancy. When not possible, practice guidelines developed by disease-specific experts should be followed.
Cancer 08/2011; 118(7):1827-37. · 4.77 Impact Factor
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Clive S Zent,
Brian J Smith,
Zuhair K Ballas,
James E Wooldridge,
Brian K Link,
Timothy G Call,
Tait D Shanafelt,
Deborah A Bowen,
Neil E Kay,
Thomas E Witzig,
George J Weiner
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ABSTRACT: CpG oligonucleotide 7909 (CpG 7909, PF-03512676), a synthetic 24mer single stranded agonist of TLR9 expressed by B cells and plasmacytoid dendritic cells, is immunomodulatory and can cause activation-induced death of chronic lymphocytic leukemia (CLL) cells. We report a phase I study of CpG 7909 in 41 patients with early relapsed CLL. A single intravenous dose of CpG 7909 was well tolerated with no clinical effects and no significant toxicity up to 1.05 mg/kg. Single dose subcutaneous CpG 7909 had a maximum tolerated dose (MTD) of 0.45 mg/kg with dose limiting toxicity of myalgia and constitutional effects. Multiple weekly subcutaneous doses at the MTD were well tolerated. CpG 7909 administration induced immunologic changes in CLL and non-malignant cells that were dose and route dependent. We conclude that multidose therapy with subcutaneous CpG 7909 (0.45 mg/kg) could be used in future phase II combination clinical trials for CLL.
Leukemia & lymphoma 08/2011; 53(2):211-7. · 2.40 Impact Factor
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Matthew J Maurer,
James R Cerhan,
Jerry A Katzmann,
Brian K Link,
Cristine Allmer, Clive S Zent,
Timothy G Call,
Kari G Rabe,
Curtis A Hanson,
Neil E Kay,
Susan L Slager,
Thomas E Witzig,
Tait D Shanafelt
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ABSTRACT: Free light chains (FLCs) are the most commonly detected paraproteins in chronic lymphocytic leukemia (CLL). We examined the types of FLC abnormalities and prognostic utility of the FLC assay compared with standard prognostic biomarkers in a prospective cohort of 339 patients with newly diagnosed CLL. Three types of FLC abnormalities were identified: monoclonal elevated FLC (elevated κ and/or λ with abnormal FLC ratio), polyclonal elevated FLC (elevated κ and/or λ with normal FLC ratio), and ratio-only FLC abnormality (normal range κ and λ with abnormal FLC ratio). One hundred sixty-five patients (49%) had a FLC abnormality with approximately equal distribution among monoclonal elevation, polyclonal elevation, and ratio-only abnormality. All FLC abnormalities were associated with poor time to first treatment: monoclonal FLC (hazard ratio [HR], 4.99; 95% confidence interval [CI], 2.94-8.48), polyclonal FLC (HR, 2.40; 95% CI, 1.24-4.64), ratio-only FLC (HR, 2.57; 95% CI, 1.40-4.69). Monoclonal FLC and polyclonal FLC were associated with poor overall survival compared with patients with normal FLC. Results remained significant after adjusting for Rai stage. The FLC assay is a simple, widely available clinical test with similar prognostic utility as routinely used prognostic biomarkers for CLL. Among persons with FLC abnormalities, the type of abnormality affects prognostic significance.
Blood 07/2011; 118(10):2821-6. · 9.90 Impact Factor
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Marek Mraz, Clive S Zent,
Amy K Church,
Diane F Jelinek,
Xiaosheng Wu,
Sarka Pospisilova,
Stephen M Ansell,
Anne J Novak,
Neil E Kay,
Thomas E Witzig,
Grzegorz S Nowakowski
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ABSTRACT: Rituximab improves the outcome of patients with non-Hodgkin lymphoma, but does not completely eradicate residual B-cell populations in the microenvironment of the bone marrow and lymph nodes. Adhesion to stromal cells can protect B-cells from apoptosis induced by chemotherapy drugs [(cell adhesion-mediated drug resistance (CAM-DR)]. A similar mechanism of resistance to rituximab has not, to our knowledge, been described. We tested the hypothesis that the microenvironment protects malignant B-cells from rituximab-induced apoptosis, and that blocking these interactions with natalizumab, an antibody targeting VLA-4 (integrin alfa-4-beta-1/CD49d), can overcome this protection. VLA-4 is an adhesion molecule constitutively expressed on malignant B-cells and is important for pro-survival signalling in the bone marrow and lymph node microenvironment. The human bone marrow stromal cell line HS-5 was shown to strongly protect B-cell lymphoma cells from rituximab cytotoxicity, suggesting the existence of a stromal cell adhesion-mediated antibody resistance (CAM-AR) mechanism analogous to CAM-DR. Natalizumab decreased B-lymphocyte adherence to fibronectin by 75-95% and partially overcame stromal protection against rituximab and cytotoxic drugs. These pre-clinical findings suggest that the addition of stromal adhesion-disruptive drugs to rituximab-containing therapy could improve treatment efficacy.
British Journal of Haematology 07/2011; 155(1):53-64. · 4.94 Impact Factor
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Clive S Zent
Leukemia & lymphoma 07/2011; 52(10):1823-4. · 2.40 Impact Factor
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ABSTRACT: CCND1-IGH@ translocation is considered pathognomonic of mantle cell lymphoma (MCL), as this distinct chromosomal abnormality has not been reported in any other subtypes of mature B-cell lymphoma. Despite this unifying cytogenetic feature, MCL encompasses 2 distinct groups: the usual MCLs with an overall survival of 3 to 5 years and the so-called "indolent non-nodal mantle cell lymphomas (INNMCLs)." The latter group of MCLs has quite distinctive clinical features, including frequent neoplastic lymphocytosis, absent peripheral lymphadenopathy, and indolent clinical courses. The clinical, biological, and molecular characteristics of INNMCL are still not well understood. Herein, we report a patient with clinical and cytogenetic features of INNMCL with overlapping morphologic and immunophenotypic features resembling hairy cell leukemia (HCL). After failing the chemotherapeutic regimen for MCL, he received a HCL-directed therapy and achieved durable response. This case suggests that CCND1-IGH@ may rarely occur in other mature B-cell neoplasms such as HCL. Further clinicopathologic studies of the so-called "INNMCL" are warranted.
The American journal of surgical pathology 07/2011; 35(7):1080-4. · 4.06 Impact Factor
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ABSTRACT: Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) is usually an incidental diagnosis in patients with early-intermediate stage disease. However, most patients with a diagnosis of CLL will subsequently have significant morbidity and die from their disease and its complications. For these patients, CLL is not the 'good leukemia' with a predictably 'benign' outcome. Indeed, we can now identify a cohort of patients with high-risk CLL at diagnosis who will have rapid disease progression, poor response to treatment, and poor survival based on prognostic methods developed from an improved understanding of the biology of CLL. The concomitant development of improved treatments has led to risk-adjusted management approaches that could improve outcomes. We discuss the clinical and laboratory components of comprehensive risk evaluation of patients with CLL and our approach to the management of patients with a high to very high risk of disease progression and poor outcome. In addition, we review the challenges and prospects for improving prognostic precision and the development of new drugs to improve the treatment of patients with CLL with a high risk of adverse outcome.
Leukemia & lymphoma 06/2011; 52(8):1425-34. · 2.40 Impact Factor
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Leukemia & lymphoma 06/2011; 52(6):946-7. · 2.40 Impact Factor
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ABSTRACT: Lymphocyte enhancer binding factor 1 (LEF-1) plays a crucial role in B lineage development and is only expressed in B cell precursors as B cell differentiation into mature B and plasma cells silences its expression. Chronic lymphocytic leukemia (CLL) cells aberrantly express LEF-1 and its expression is required for cellular survival. We hypothesized that modification of the differentiation status of CLL cells would result in loss of LEF-1 expression and eliminate the survival advantage provided by its aberrant expression. In this study, we first established a methodology that induces CLL cells to differentiate into immunoglobulin (Ig) secreting cells (ISC) using the TLR9 agonist, CpG, together with cytokines (CpG/c). CpG/c stimulation resulted in dramatic CLL cell phenotypic and morphologic changes, expression of cytoplasmic Ig, and secretion of light chain restricted Ig. CpG/c stimulation also resulted in decreased CLL cell LEF-1 expression and increased Blimp-1 expression, which is crucial for plasma cell differentiation. Further, Wnt pathway activation and cellular survival were impaired in differentiated CLL cells compared to undifferentiated CLL cells. These data support the notion that CLL can differentiate into ISC and that this triggers decreased leukemic cell survival secondary to the down regulation of LEF-1 and decreased Wnt pathway activation.
PLoS ONE 01/2011; 6(10):e26056. · 4.09 Impact Factor
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Tait D Shanafelt,
Matthew T Drake,
Matthew J Maurer,
Cristine Allmer,
Kari G Rabe,
Susan L Slager,
George J Weiner,
Timothy G Call,
Brian K Link, Clive S Zent,
Neil E Kay,
Curtis A Hanson,
Thomas E Witzig,
James R Cerhan
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ABSTRACT: Vitamin D insufficiency is common globally and low levels are linked to higher cancer incidence. Although vitamin D insufficiency is related to inferior prognosis in some cancers, no data exist for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). We evaluated the relationship of 25(OH)D serum levels with time-to-treatment (TTT) and overall survival (OS) in newly diagnosed CLL patients participating in a prospective cohort study (discovery cohort) and a separate cohort of previously untreated patients participating in an observational study (confirmation cohort). Of 390 CLL patients in the discovery cohort, 119 (30.5%) were 25(OH)D insufficient. After a median follow-up of 3 years, TTT (hazard ratio[HR] = 1.66; P = .005) and OS (HR = 2.39; P = .01) were shorter for 25(OH)D-insufficient patients. In the validation cohort, 61 of 153 patients (39.9%) were 25(OH)D insufficient. After a median follow-up of 9.9 years, TTT (HR = 1.59; P = .05) and OS (HR 1.63; P = .06) were again shorter for 25(OH)D-insufficient patients. On pooled multivariable analysis of patients in both cohorts adjusting for age, sex, Rai stage, CD38 status, ZAP-70 status, immunoglobulin heavy chain variable (IGHV) gene mutation status, CD49d status, and cytogenetic abnormalities assessed by interphase fluorescent in situ hybridization testing, 25(OH)D insufficiency remained an independent predictor of TTT (HR = 1.47; P = .008), although the association with OS was not significant (HR = 1.47; P = .07). Vitamin D insufficiency is associated with inferior TTT and OS in CLL patients. Whether normalizing vitamin D levels in deficient CLL patients would improve outcome merits clinical testing.
Blood 11/2010; 117(5):1492-8. · 9.90 Impact Factor
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Tait D Shanafelt,
Kari G Rabe,
Neil E Kay, Clive S Zent,
Diane F Jelinek,
Megan S Reinalda,
Susan M Schwager,
Debbie A Bowen,
Susan L Slager,
Curtis A Hanson,
Timothy G Call
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ABSTRACT: A study was undertaken to analyze the survival of chronic lymphocytic leukemia (CLL) patients relative to age-matched individuals in the general population and determine the age-stratified utility of prognostic testing.
All 2487 patients diagnosed with CLL between January 1995 and June 2008 and cared for in the Mayo Clinic Division of Hematology were categorized by age at diagnosis and evaluated for differences in clinical characteristics, time to first treatment, and overall survival (OS).
Among Rai stage 0 patients, survival was shorter than the age-matched general population for patients aged <55 years (P < .001), 55 to 64 years (P < .001), and 65 to 74 years (P < .001), but not those aged ≥75 years at diagnosis (P = not significant). CD38, IGHV mutation, and ZAP-70 each predicted time to first treatment independent of stage for all age groups (all P < .04), but had less value for predicting OS, particularly as age increased. IGHV and fluorescent in situ hybridization (FISH) predicted OS independent of stage for patients aged <55 years (P ≤ .001), 55 to 64 years (P ≤ .004), and 65 to 74 years (P ≤ .001), but not those aged ≥75 years. CD38 and ZAP-70 each predicted OS independent of stage for only 2 of 4 age categories. Among Rai 0 patients aged <75 years, survival was shorter than the age-matched population only for IGHV unmutated (P < .001) patients or those with unfavorable FISH (P < .001).
Survival of CLL patients aged <75 years is shorter than the age-matched general population regardless of disease stage. Among patients aged <75 years, the simple combinations of stage and IGHV or stage and FISH identifies those with excess risk of death relative to the age-matched population. Although useful for predicting time to first treatment independent of stage for patients of all ages, prognostic testing had little utility for predicting OS independent of stage among patients aged ≥75 years.
Cancer 10/2010; 116(20):4777-87. · 4.77 Impact Factor
