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Presentation Serum Selenium Predicts for Overall Survival, Dose Delivery, and First Treatment Response in Aggressive Non-Hodgkin’s Lymphoma

Kim W. Last, Victoria Cornelius, Trevor Delves, Christine Sieniawska, Jude Fitzgibbon, Andrew Norton, John Amess, Andy Wilson, Ama Z.S. Rohatiner, T. Andrew Lister

From the Cancer Research UK Medical Oncology Unit, Department of Medical Oncology, St Bartholomew’s Hospital, London; Cancer Research UK Department of Statistics, Oxford; Trace Elements Unit, Southampton General Hospital, Southampton, United Kingdom.

Address reprint requests to Kim W. Last, MD, Cancer Research UK Medical Oncology Unit, Department of Medical Oncology, 45 Little Britain, St Bartholomew’s Hospital, London EC1M 6BQ, United Kingdom; email: kim.last{at}cancer.org.uk.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Purpose: This study was undertaken to test the hypothesis that serum selenium concentration at presentation correlates with dose delivery, first treatment response, and overall survival in patients with aggressive B-cell non-Hodgkin’s lymphoma.

Patients and Methods: The patients presented between July 1986 and March 1999 and received anthracycline-based chemotherapy, radiotherapy, or both. The total selenium content was retrospectively analyzed in 100 sera, frozen at presentation, using inductively coupled plasma mass spectrometry.

Results: The serum selenium concentration ranged from 0.33 to 1.51 µmol/L (mean, 0.92 µmol/L; United Kingdom adult reference range, 1.07 to 1.88 µmol/L). Serum selenium concentration correlated closely with performance status but with no other clinical variable. Multivariate analysis revealed that increased dose delivery, summarized by an area under the curve, correlated positively with younger age (P < .001), advanced stage (P = .001), and higher serum selenium concentration (P = .032). Selenium level also correlated positively with response (odds ratio, 0.62; 95% confidence interval [CI], 0.43 to 0.90; P = .011) and achievement of long-term remission after first treatment (log-rank test, 4.38; P = .036). On multivariate analysis, selenium concentration was positively predictive of overall survival (hazard ratio [HR], 0.76 for 0.2 µmol/L increase; 95% CI, 0.60 to 0.95; P = .018), whereas age indicated negative borderline significance (HR, 1.09; 95% CI, 0.99 to 1.18; P = .066).

Conclusion: Serum selenium concentration at presentation is a prognostic factor, predicting positively for dose delivery, treatment response, and long-term survival in aggressive non-Hodgkin’s lymphoma. Unlike most existing prognostic factors in aggressive non-Hodgkin’s lymphoma, selenium supplementation may offer a novel therapeutic strategy in this frequently curable malignancy.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
SELENIUM IS an essential trace element in humans, best known for its function as an antioxidant. With the classification of selenocysteine as the 21st amino acid in 1988,^1,2 and the increase in the number of discovered selenoproteins to 40, selenium is increasingly considered to be important to human physiology; conversely, its deficiency is considered to be important to the pathophysiology of conditions ranging from depression to atherosclerosis to cancer.³

A possible protective effect of selenium against human malignancy was first suggested in 1969, after the observation of a decreased cancer incidence in populations within the United States with a higher selenium intake.⁴ Subsequent epidemiologic evidence in support of this hypothesis has been equivocal. Two important epidemiologic studies, however, have led many to believe that an association exists. In the United States, an inverse relationship between forage-crop selenium and county cancer incidence was observed⁵ and examination of the dietary intake of selenium in more than 25 countries found an inverse correlation with total age-adjusted cancer mortality.⁶

More recently, data from intervention studies have lent support to the role of selenium in human cancer prevention. In two trials published to date, selenium was given as the sole chemopreventive agent. The first was a population-based study in an area of China with low selenium intake, a 15% prevalence rate of hepatitis B, and an incidence of primary liver cancer of 50/10,000/annum.⁷ After 8 years of intervention with selenized table salt, the incidence of primary liver cancer had decreased by 35% in the intervention township versus the nonsupplemented control townships. In the second study, patients with a history of nonmelanomatous skin cancer were treated for a mean of 4 years with placebo or selenium (as selenized brewer’s yeast).⁸ Selenium supplementation was found to be significantly associated with reductions in the secondary end points of total cancer incidence and total cancer mortality. The primary end point, a reduction in basal and squamous cell carcinoma incidence, was not reached. In the laboratory, in vitro and in vivo experiments have revealed that selenium compounds can exert cytotoxic activity, synergize with cytotoxic agents, and favorably influence cancer cell phenotype.^9–11 No clinical evidence confirming selenium as a disease modifier in cancer so far exists. However, the reduction in cisplatin-induced bone marrow and renal toxicity by selenium supplementation, and the amelioration of doxorubicin cardiomyocyte toxicity by an organic selenium compound, indicate that selenium status may affect chemotherapy dose delivery in cancer and lymphoma patients.^12–14

This study was undertaken to test the hypothesis that serum selenium at presentation would predict for response to first treatment, dose delivery, and overall survival in patients with high-grade, B-cell, non-Hodgkin’s lymphoma, the most common non-Hodgkin’s lymphoma.¹⁵ If proven, the argument for exploration of selenium compounds as a therapy adjunct to aid improvement of the long-term remission rate of only 40% to 50% in this illness would be strengthened. Indirect evidence supporting an association between selenium and the clinical course of lymphoma comes from a study indicating that pretreatment serum selenium concentration correlated with response to treatment in a group of 51 epidermotropic T-cell lymphomas¹⁶ and the observation that serum selenium levels were significantly lower in patients with non-Hodgkin’s lymphoma than in normal controls.¹⁷

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patients
Patient samples were selected on the basis of an original diagnosis of high-grade, B-cell, non-Hodgkin’s lymphoma and the availability of heme-free frozen sera. Of the 383 patients treated at St Bartholomew’s Hospital between July 1986 and March 1999 for high-grade, B-cell, non-Hodgkin’s lymphoma, 143 had sera frozen at diagnosis; 100 heme-free sera were still available. The overall survival of the 283 patients without suitable sera was the same as that of the 100 patients studied (Fig 1). Histology review of the 100 samples investigated by one of the authors (A.N.) according to the new World Health Organization classification was as follows: diffuse large B-cell lymphoma (DLBCL), 77 samples; mediastinal large B-cell lymphoma, 14 samples; DLBCL, T-cell–rich, three samples; lymphoplasmacytic lymphoma with a high content of blasts, two samples; angioimmunoblastic T-cell lymphoma, two samples; Burkitt’s lymphoma, one sample; and mantle-cell lymphoma with a high content of blasts, one sample. Fifteen patients had composite or discordant histology at presentation (eight with evidence of follicular lymphoma, one with evidence of lymphoplasmacytic lymphoma, two with evidence of unclassifiable low-grade non-Hodgkin’s lymphoma, and four with evidence of marginal zone lymphoma of mucosa-associated lymphoid tissue type). Clinical information was prospectively collected as part of the department’s clinical database. Where necessary, additional treatment administration details were retrieved from patient records. Presentation clinical variables investigated for an association with either overall survival, response to first treatment, or dose delivery were serum selenium, age, sex, B symptoms, stage, retrospective performance status, lactate dehydrogenase (or hydroxybutyrate dehydrogenase if the patient presented before mid-1989), and number of extranodal sites of disease (Table 1). As the best available current predictor of overall survival, the International Prognostic Index (IPI) score was calculated for the 95 patients with complete IPI data (Table 1).¹⁸

View larger version (17K): [in this window] [in a new window]   Fig 1. Overall survival, from diagnosis, of the 283 patients treated between July 1986 and March 1999 without available presentation frozen sera and the 100 patients investigated.

Selenium Concentration Measurement
Total selenium content of the sera was measured using inductively coupled plasma mass spectrometry. Selenium-78 was determined after a 1 in 15 dilution with a diluent containing 0.5% butan-1-ol, which minimized interference from argon adducts, and tellurium as an internal standard to compensate for instrumental fluctuations.²² However, high concentrations of iodine (> 3,000 µmol/L) in five samples analyzed produced spectral overlap from hydrogen-1–iodine-127 with the tellurium-128 isotope monitored. For these samples, indium-115 was used as the internal standard. The calibration was carried out using matrix-matched standards containing bovine serum. Internal quality control sera were prepared by adding selenium to bovine sera at 0.2, 0.6, 1.2, and 1.7 µmol/L. These were analyzed with every 10 duplicate test samples, providing a between-run precision that ranged from 3.7% to 5.9% relative SD, and a within-run precision of 9.3% to 2.3%, over the concentration range 0.25 to ± 1.75 µmol/L selenium. Analysis of a certified quality control serum (Seronorm 704121, SERO AS, Asker, Norway), with an assigned value of 0.92 mmol/L as measured by electrothermal atomic absorption spectrometry, gave a daily mean variation of 0.93 ± 0.03 mmol/L throughout the analysis of the samples. External quality control was provided by participation in two quality assessment schemes from Centre du Toxicologie de Quebec (Canada) and Trace Element Quality Assurance Scheme (UK-TEQAS, University of Surrey, Guildford, United Kingdom).

Statistical Methods
Area under the curve summary measure, AUC_ratio. A summary measure for dose delivery was calculated and the relationship with patient variables was explored using linear regression. The usual dose summary measures (eg, relative dose-intensity, cumulative dose) were not satisfactory summary statistics for this application because of the variation in dosing schedules (both in quantity and time duration). Instead, an adaptation of the standard AUC measure, often used to summarize serial measurements, was applied.²³ The AUC was calculated using the trapezium rule. For a schedule of n doses, where the proportion of cumulative dose at time t(i) was y(i) (where i = 1 to n), the AUC was defined as

(1)

Dose-delivery associations were sought for doxorubicin, cyclophosphamide, and vincristine. Data are shown for doxorubicin only because the findings for cyclophosphamide and vincristine were comparable. Each patient had a planned chemotherapy schedule determined by the regimen prescribed. After treatment was completed, the patient’s actual schedule was available, which differed from the planned schedule when drug doses and dates were modified. The proportion of the cumulative dose was plotted against time for both the planned and the actual dosing schedules. The area under the planned and actual curves (AUC_planned, AUC_actual) was then calculated. The summary measure used, AUC_ratio, represents AUC_actual divided by AUC_planned and is thus a measure of the proportion of actual dose to planned dose over the duration of the treatment time. If the planned schedule was administered, the AUC_ratio was 1; if a full planned dose was not given or a dose was delayed, then AUC_ratio decreased. If doses were given after the final planned time, then the time axis for the planned regimen was extended and the contribution was weighted using

(2)

where t₁ is the time from the first planned dose to final planned dose, t₂ is the time from the first administered dose to the final administered dose, and n is the number of planned doses. Where treatment stopped early because of death or disease progression, the planned dose intensity was censored at the time of death or disease progression.

Variables included in the multivariate model for dose delivery were selected using a stepwise procedure. Age and selenium were treated as continuous variables and the remaining variables were treated as categorical. Variables were included in the Cox and logistic regression model if they indicated significance at the univariate level (P < .1). Analysis of residuals was performed to check model assumptions.

Response Analysis
Response was categorized according to the local criteria in use at the time.²⁴ The response criteria used predate the 1997 consensus statement.²⁵ The definitions for complete response (CR) are the same, whereas good partial response (GPR) is comparable to CR_uncertain and poor partial response (PPR) is comparable to partial response. Response was grouped according to similar overall survivals: CR/GPR and PPR, treatment failure, or treatment-related death (Fig 2). The ² and t tests were used to compare groups at the univariate level and logistic regression was fitted to estimate the odds ratio. The patients were divided into quartiles as defined by presentation serum selenium concentration, and tested univariately with regard to response and response duration. Remission duration was defined as time to relapse or death from documentation of response to first treatment.

View larger version (20K): [in this window] [in a new window]   Fig 2. Overall survival of the 100 patients grouped according to response to first treatment, from response documentation.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
The presentation serum selenium concentration was normally distributed for the 100 patients, with a mean of 0.92 µmol/L (SD, 0.25 µmol/L) and range of 0.33 to 1.51 µmol/L. A trend of decreasing mean serum selenium was observed with increasing year of presentation. Seventy-three patients had a selenium level below the United Kingdom reference range from the early 1980s (United Kingdom adult reference range, 1.07 to 1.88 µmol/L²⁷). Serum selenium concentration correlated closely with performance status but no other clinical variable (P < .001, data not shown). As a consequence of this association, only one of these variables was included in the multivariate analyses at the same time because the variables explain similar variation. Our primary interest was in assessing the relationship between selenium levels, response, dose delivery, and survival rather than developing a new prognostic model. As a result, the multivariate analyses containing the selenium variable are presented here. Exchanging selenium with performance status gave similar results.

Dose Delivery
In the 87 chemotherapy patients with complete treatment data, there were 128 treatment delays or dose reductions (or both) associated with 42 in-patient episodes for neutropenic fever or sepsis, 28 admissions for other treatment-related complications, 45 episodes of neutropenia without fever, and 13 delays for other reasons. Stage and serum selenium positively and age-negatively correlated with the dose-delivery summary measure AUC_ratio at the univariate level (Table 2). These three variables were then selected by a stepwise procedure for the multivariate model. The results indicate that a significantly better dose delivery (summarized by AUC_ratio) correlated positively with younger age, advanced stage, and higher serum selenium (Table 3).

Overall Survival
The calculated median overall survival of the 100 patients was 6.2 years (range, 1 week to 13 years; 95% CI, 1.9 to 10.7). Completeness of follow-up data was confirmed because the actual median overall survival of the 51 surviving patients was almost identical at 6.1 years (range, 4 months [one patient lost to follow-up at 4 months] to 13.5 years). When IPI was considered as a continuous variable, it was found to be prognostic with regard to overall survival, with a hazard ratio of 1.58 (95% CI, 1.18 to 2.13). The results of univariate analysis indicated that age, selenium concentration, sex, stage, and performance status correlated with survival time (Table 2). On multivariate analysis, using a Cox model, selenium was the most significant factor, with a hazard ratio of 0.76 for every increase of 0.2 µmol/L in serum selenium level; that is, a higher serum selenium concentration correlated with longer survival (Table 3). For example, a patient with a serum selenium concentration of 1.0 µmol/L had a 24% lower risk of death than a patient with a concentration of 0.8 µmol/L, over the duration of the study. Replacing selenium with performance status gave similar results; that is, a decrease in performance status was significantly associated with shorter survival (data not shown). Overall survival for each selenium quartile is displayed in Fig 3.

View larger version (18K): [in this window] [in a new window]   Fig 3. Overall survival, from diagnosis, of the 100 patients split into serum selenium quartiles.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

Several compatible mechanisms may underlie the prediction of dose delivery, response, and outcome by presentation serum selenium. These include prevention of chemoresistance, enhancement of immune function, direct cytotoxic activity of selenium compounds, and reduction of treatment-related side effects. Selenomethionine prevented cisplatin resistance when administered in vitro and to nude mice with tumors derived from the same ovarian cancer cell line.¹¹ In addition, in a murine model, using Dalton’s lymphoma, preinoculation with selenomethionine increased survival by 31% and 112% compared with those mice that received selenomethionine at inoculation and those that received no selenomethionine supplementation, respectively.²⁸ Multiple processes are likely to account for this survival advantage.

Evidence indicating a role for selenium in immune response enhancement includes a study in which selenite, given to volunteers with normal selenium levels, resulted in clonal expansion of activated T cells in response to in vitro incubation with a cancer cell line. T-cell cytotoxicity increased by 118% and natural-killer cell–mediated lytic activity increased by 82% compared with baseline (P < .05).^29,30 In vitro, selenium compounds produce direct antitumor effects, as demonstrated by tumor cell growth inhibition and apoptosis promotion,¹⁰ and exhibit synergy with the cytotoxic agents paclitaxel and doxorubicin (in terms of increased cell death and growth arrest) in the majority of cell lines investigated by Vadgama et al.⁹ It is possible that selenium enhances dose delivery by reducing the side effects of therapy. Selenium supplementation has been shown to reduce cisplatin-induced nephrotoxicity and bone marrow suppression in a crossover patient study, and to prevent doxorubicin-induced cardiomyocyte cytotoxicity in vitro.^12,14

Performance status was the only clinical variable that correlated closely with serum selenium. This correlation may be the result of general nutritional deficiency in the months and weeks before diagnosis or an acute phase response of serum selenium to illness.³¹ The associations found in this study could therefore be due to a bystander phenomenon with no causality related to selenium level. Alternatively, the correlations described may indeed reflect a causal relationship and account, in part, for the predictive power of performance status in aggressive non-Hodgkin’s lymphoma. Regarding the possibility that the low selenium values seen in this study are partly due to an acute phase response, this need not imply lack of causality or scope for therapeutic intervention. For example, the low serum selenium levels seen in patients with acute pancreatitis have been reported to respond to supranutritional intravenous infusions of selenium, resulting in a marked decline in the mortality rate associated with this frequently fatal condition.^32,33

The majority of the patients investigated (73%) had a serum selenium concentration below the United Kingdom reference range from the early 1980s. This finding is consistent with the reporting of lower selenium levels in cancer and lymphoma patients compared with the general population,^17,34 with the decline in selenium intake in the United Kingdom population since this reference range was generated (attributed to the cessation of Canadian wheat importation),^35,36 and with the aforementioned decrease in serum selenium as part of the acute phase response to illness.³¹

The extent of selenium deficiency in aggressive non-Hodgkin’s lymphoma patients (as assessed by serum selenium levels) who come from general populations replete in selenium remains to be seen. Selenium levels vary throughout the world from extremely low in areas of China, to low in many parts of Europe, to the high-normal levels in most areas of North America. If selenium is important in aggressive non-Hodgkin’s lymphoma phenotype evolution and treatment success, countries with a high-normal selenium level in the population might be expected to have a better overall survival for aggressive non-Hodgkin’s lymphoma than countries with a low selenium intake. This is not apparent, because United Kingdom survival rates are comparable to those in North America. Whether this reflects the need for supernormal selenium intakes to alter disease outcome at the population level or reflects aggressive non-Hodgkin’s lymphoma resulting in low selenium levels regardless of premorbid selenium status will require additional investigation.

The selenium cancer chemoprevention study, performed in former nonmelanomatous skin cancer patients, took place in the United States.⁸ Selenium supplementation was beneficial even in those replete in the micronutrient, although the benefit was greatest in the lower tertile of patients (serum selenium < 1.35 µmol/L).³⁷ All but three patients in our study had a serum selenium concentration within Clark’s lower tertile.

Prospective, multicenter or multicountry substantiation of the findings described will be required. The discovery of presentation serum selenium as a potential prognostic factor in aggressive non-Hodgkin’s lymphoma is intriguing. Our results, in conjunction with the chemopreventive and laboratory data reviewed, indicate that incorporation of selenium into an overall therapeutic strategy is worthy of study, with the aim to improve prognosis in this frequently curable malignancy.

	ACKNOWLEDGMENTS

 
We thank Margaret Rayman, University of Surrey, United Kingdom, for comments on the manuscript, and the radiology department and many staff members at St Bartholomew’s hospital involved in caring for the patients studied.

	NOTES

 
Supported by Cancer Research UK, Lincoln’s Inn Fields, London, UK.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
1. Leinfelder W, Zehelein E, Mandrand-Berthelot MA, et al: Gene for a novel tRNA species that accepts L-serine and cotranslationally inserts selenocysteine. Nature 331:723–725, 1988[CrossRef][Medline]

2. Soll D: Genetic code: Enter a new amino acid. Nature 331:662–663, 1988[Medline]

3. Rayman MP: The importance of selenium to human health. Lancet 356:233–241, 2000[CrossRef][Medline]

4. Shamberger RJ, Frost DV: Possible protective effect of selenium against human cancer. Can Med Assoc J 100:682, 1969[Medline]

5. Clark LC, Cantor KP, Allaway WH: Selenium in forage crops and cancer mortality in U.S. counties. Arch Environ Health 46:37–42, 1991[Medline]

6. Schrauzer GN, White DA, Schneider CJ: Cancer mortality correlation studies: III. Statistical associations with dietary selenium intakes. Bioinorg Chem 7:23–31, 1977[CrossRef][Medline]

7. Yu SY, Zhu YJ, Li WG: Protective role of selenium against hepatitis B virus and primary liver cancer in Qidong. Biol Trace Elem Res 56:117–124, 1997[Medline]

8. Clark LC, Combs GF Jr, Turnbull BW, et al: Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin: A randomized controlled trial—Nutritional Prevention of Cancer Study Group. JAMA 276:1957–1963, 1996[Abstract/Free Full Text]

9. Vadgama JV, Wu Y, Shen D, et al: Effect of selenium in combination with Adriamycin or Taxol on several different cancer cells. Anticancer Res 20:1391–1414, 2000[Medline]

10. Thompson HJ, Wilson A, Lu J, et al: Comparison of the effects of an organic and an inorganic form of selenium on a mammary carcinoma cell line. Carcinogenesis 15:183–186, 1994[Abstract/Free Full Text]

11. Caffrey PB, Frenkel GD: Selenium compounds prevent the induction of drug resistance by cisplatin in human ovarian tumor xenografts in vivo. Cancer Chemother Pharmacol 46:74–78, 2000[CrossRef][Medline]

12. Hu YJ, Chen Y, Zhang YQ, et al: The protective role of selenium on the toxicity of cisplatin-contained chemotherapy regimen in cancer patients. Biol Trace Elem Res 56:331–341, 1997[Medline]

13. Yoshida M, Iizuka K, Terada A, et al: Prevention of nephrotoxicity of cisplatin by repeated oral administration of ebselen in rats. Tohoku J Exp Med 191:209–220, 2000[CrossRef][Medline]

14. Kotamraju S, Konorev EA, Joseph J, et al: Doxorubicin-induced apoptosis in endothelial cells and cardiomyocytes is ameliorated by nitrone spin traps and ebselen: Role of reactive oxygen and nitrogen species. J Biol Chem 275:33585–33592, 2000[Abstract/Free Full Text]

15. Armitage JO, Weisenburger DD: New approach to classifying non-Hodgkin’s lymphomas: Clinical features of the major histologic subtypes—Non-Hodgkin’s Lymphoma Classification Project. J Clin Oncol 16:2780–2795, 1998[Abstract]

16. Deffuant C, Celerier P, Boiteau HL, et al: Serum selenium in melanoma and epidermotropic cutaneous T-cell lymphoma. Acta Derm Venereol 74:90–92, 1994[Medline]

17. Avanzini P, Vinceti M, Ilariucci F, et al: Serum selenium concentrations in patients with newly diagnosed lymphoid malignancies. Haematologica 80:505–511, 1995[Abstract/Free Full Text]

18. A predictive model for aggressive non-Hodgkin’s lymphoma: The International Non-Hodgkin’s Lymphoma Prognostic Factors Project. N Engl J Med 329:987–994, 1993[Abstract/Free Full Text]

19. Radford JA, Whelan JS, Rohatiner AZ, et al: Weekly VAPEC-B chemotherapy for high grade non-Hodgkin’s lymphoma: Results of treatment in 184 patients. Ann Oncol 5:147–151, 1994[Abstract/Free Full Text]

20. McKelvey EM, Gottlieb JA, Wilson HE, et al: Hydroxydaunomycin (Adriamycin) combination chemotherapy in malignant lymphoma. Cancer 38:1484–1493, 1976[CrossRef][Medline]

21. Klimo P, Connors JM: MACOP-B chemotherapy for the treatment of diffuse large-cell lymphoma. Ann Intern Med 102:596–602, 1985[Abstract/Free Full Text]

22. Delves HT, Sieniawska C: Simple method for the accurate determination of selenium in serum by using ICP-MS. J Anal At Spectrom 12:387–389, 1997[CrossRef]

23. Matthews JN, Altman DG, Campbell MJ, et al: Analysis of serial measurements in medical research. BMJ 300:230–235, 1990[Abstract/Free Full Text]

24. Dhaliwal HS, Rohatiner AZ, Gregory W, et al: Combination chemotherapy for intermediate and high grade non-Hodgkin’s lymphoma. Br J Cancer 68:767–774, 1993[Medline]

25. Cheson BD, Horning SJ, Coiffier B, et al: Report of an international workshop to standardize response criteria for non-Hodgkin’s lymphomas: NCI Sponsored International Working Group. J Clin Oncol 17:1244–1253, 1999[Abstract/Free Full Text]

26. Cox DR: Regression models and life tables. J R Stat Soc (B) 34:187–220, 1972

27. Lloyd B, Lloyd RS, Clayton BE: Effect of smoking, alcohol, and other factors on the selenium status of a healthy population. J Epidemiol Community Health 37:213–217, 1983[Abstract/Free Full Text]

28. Rana MP, Sardar S, Chatterjee M: Selenomethionine in the inhibition of a transplantable murine lymphoma: Reflection on hepatic drug metabolizing enzymes. Tumour Biol 17:102–109, 1996[Medline]

29. Kiremidjian-Schumacher L, Roy M, Wishe HI, et al: Supplementation with selenium and human immune cell functions: II. Effect on cytotoxic lymphocytes and natural killer cells. Biol Trace Elem Res 41:115–127, 1994[Medline]

30. Roy M, Kiremidjian-Schumacher L, Wishe HI, et al: Supplementation with selenium and human immune cell functions: I. Effect on lymphocyte proliferation and interleukin 2 receptor expression. Biol Trace Elem Res 41:103–114, 1994[Medline]

31. Nichol C, Herdman J, Sattar N, et al: Changes in the concentrations of plasma selenium and selenoproteins after minor elective surgery: Further evidence for a negative acute phase response? Clin Chem 44:1764–1766, 1998[Free Full Text]

32. Kuklinski B, Buchner M, Schweder R, et al: [Acute pancreatitis: A free radical disease—Decrease in fatality with sodium selenite (Na₂SeO₃) therapy]. Z Gesamte Inn Med 46:145–149, 1991[Medline]

33. Kuklinski B, Zimmermann T, Schweder R: [Decreasing mortality in acute pancreatitis with sodium selenite: Clinical results of 4 years antioxidant therapy]. Med Klin 90:36–41, 1995 (suppl 1)

34. Alaejos MS, Diaz Romero FJ, Diaz Romero C: Selenium and cancer: Some nutritional aspects. Nutrition 16:376–383, 2000[CrossRef][Medline]

35. Joint Food Safety and Standards Group: Food Surveillance Information Sheet 126. London, United Kingdom. Dietary intake of selenium. Ministry of Agriculture, Fisheries and Food, 1997

36. Joint Food Safety and Standards Group: Food Surveillance Information Sheet 191. London, United Kingdom. 1997 Total diet study-Aluminum, arsenic, cadmium, chromium, copper lead, mercury, nickel, selenium, tin and zinc. Ministry of Agriculture, Fisheries and Food, 1999

37. Rayman MP, Clark LC: Selenium in cancer prevention, in Rousel AM, Favier A, Anderson RA (eds): Trace Elements in Man and Animals 10: Proceedings of the 10th International Symposium on Trace Elements in Man and Animals. New York, Plenum Press, 2000, pp 575–580

Submitted June 25, 2002; accepted March 26, 2003.

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