ABSTRACT: A concurrent multicenter, randomized Phase II trial employing a recombinant poxviral vaccine provided evidence of enhanced median overall survival (OS) (p = 0.0061) in patients with metastatic castrate-resistant prostate cancer (mCRPC). The study reported here employed the identical vaccine in mCRPC to investigate the influence of GM-CSF with vaccine, and the influence of immunologic and prognostic factors on median OS. Thirty-two patients were vaccinated once with recombinant vaccinia containing the transgenes for prostate-specific antigen (PSA) and three costimulatory molecules. Patients received boosters with recombinant fowlpox containing the same four transgenes. Twelve of 32 patients showed declines in serum PSA post-vaccination and 2/12 showed decreases in index lesions. Median OS was 26.6 months (predicted median OS by the Halabi nomogram was 17.4 months). Patients with greater PSA-specific T-cell responses showed a trend (p = 0.055) toward enhanced survival. There was no difference in T-cell responses or survival in cohorts of patients receiving GM-CSF versus no GM-CSF. Patients with a Halabi predicted survival of <18 months (median predicted 12.3 months) had an actual median OS of 14.6 months, while those with a Halabi predicted survival of > or =18 months (median predicted survival 20.9 months) will meet or exceed 37.3 months, with 12/15 patients living longer than predicted (p = 0.035). Treg suppressive function was shown to decrease following vaccine in patients surviving longer than predicted, and increase in patients surviving less than predicted. This hypothesis-generating study provides evidence that patients with more indolent mCRPC (Halabi predicted survival > or =18 months) may best benefit from vaccine therapy.
Cancer Immunology and Immunotherapy 11/2009; 59(5):663-74. · 3.70 Impact Factor
ABSTRACT: New gene expressed in prostate (NGEP) is a prostate-specific gene encoding either a small cytoplasmic protein (NGEP-S) or a larger polytopic membrane protein (NGEP-L). NGEP-L expression is detectable only in prostate cancer, benign prostatic hyperplasia and normal prostate. We have identified an HLA-A2 binding NGEP epitope (designated P703) which was used to generate T cell lines from several patients with localized and metastatic prostate cancer. These T cell lines were able to specifically lyse HLA-A2 and NGEP-expressing human tumor cells. NGEP-P703 tetramer binding assays demonstrated that metastatic prostate cancer patients had a higher frequency of NGEP-specific T cells when compared with healthy donors. Moreover, an increased frequency of NGEP-specific T cells was detected in the peripheral blood mononuclear cells of prostate cancer patients post-vaccination with a PSA-based vaccine, further indicating the immunogenicity of NGEP. These studies thus identify NGEP as a potential target for T cell-mediated immunotherapy of prostate cancer.
Cancer Immunology and Immunotherapy 07/2009; 59(1):63-71. · 3.70 Impact Factor
ABSTRACT: The effect of standard or high dialysis dose and low or high dialysis flux on nutritional status was ascertained in 1846 maintenance hemodialysis patients enrolled in the HEMO Study.
Serum albumin levels, equilibrated protein catabolic rate, and postdialysis weight were obtained monthly, while adjusted protein and energy intake, self-reported appetite assessment, upper arm circumference, and calf circumference were obtained yearly. To account for patient attrition due to death or transfer, three statistical models were used to test the effects of the study interventions on longitudinal changes in nutritional parameters.
During the first 3 years of follow-up, neither mean serum albumin levels, which declined by 0.21 g/dL, nor mean postdialysis weight, which declined by 2.7 kg, were significantly affected by either study intervention. Mean levels of all anthropometric measures declined during follow-up. For years 1, 2, and 3, the mean +/- SE declines in upper arm and calf circumferences were 0.35 +/- 0.16 cm (P= 0.031) and 0.31 +/- 0.13 (P= 0.015) cm less, respectively, in the high flux compared to the low flux group. Appetite scores and mean equilibrated protein catabolic rate also declined in all randomized groups; however, the average decline in equilibrated protein catabolic rate during years 1, 2, and 3 was 0.019 +/- 0.007 g/kg/day less in the high dose than the standard dose group (P= 0.007). There was no significant change in either mean energy or protein intake from diet records over time, and neither parameter was affected by the study interventions.
Although the dose and flux interventions may subtly influence certain nutritional parameters, neither intervention prevented deterioration in nutritional status over time.
Kidney International 07/2004; 65(6):2321-34. · 6.61 Impact Factor
ABSTRACT: The effect of dialysis dose and membrane flux on nutritional parameters in hemodialysis patients: Results of the HEMO Study.Background The effect of standard or high dialysis dose and low or high dialysis flux on nutritional status was ascertained in 1846 maintenance hemodialysis patients enrolled in the HEMO Study.
Kidney International 05/2004; 65(6):2321-2334. · 6.61 Impact Factor
ABSTRACT: To evaluate differences between dietary energy intake (DEI), dietary protein intake (DPI), appetite, dietary patterns, and eating habits during dialysis treatment days (DD) and non-dialysis treatment days (NDD) in 1,901 adults receiving maintenance hemodialysis who were enrolled in the baseline phase of the National Institutes of Health-sponsored Hemodialysis (HEMO) study.
A cross-sectional analysis of participants at baseline (before randomization).
Fifteen clinical centers across the United States.
DEI, DPI, and self-reported assessment of appetite, dietary patterns, and eating habits.
For the entire study cohort, total mean (+/- SD) DEI (1,566 +/- 636 kcal/day) and weight-adjusted DEI (23.2 +/- 9.5 kcal/kg/day) were significantly higher (P <.0001) on NDD than on DD (1,488 +/- 620 kcal/day and 22.2 +/- 9.6 kcal/kg/day), respectively. Similarly, DPI was significantly higher (P <.0001) on NDD (65.0 +/- 29.0 g/day and 0.96 +/- 0.43 g/kg/day) than on DD (60.2 +/- 26.5 g/day and 0.90 +/- 0.41 g/kg/day). On DD and NDD, the mean weight-adjusted DEI for the entire cohort was less than the HEMO study standard of care (SOC) of > or =28 kcal/kg/day, whereas on NDD, several subgroups reported dietary protein intakes that were closer to the study's SOC. These included men, patients under 50 years of age, nonblack participants, those without diabetes, those with a normal or mild Index of Co-Existing Disease score, and those on dialysis for more than 5 years. Protein and energy intakes declined with worsening self-reported appetites in both DD and NDD after adjusting for other subgroup effects.
Dietary energy and protein intakes of HEMO study participants were lower on DD than on NDD, and also lower than the SOC on both days, particularly with regard to energy intake. People receiving maintenance hemodialysis should be counseled to consume adequate amounts of energy and protein daily, especially on DD. Practitioners should monitor closely those patients who report poor appetite and should intervene appropriately.
Journal of Renal Nutrition 07/2003; 13(3):191-8. · 1.57 Impact Factor
ABSTRACT: A Phase I trial of recombinant vaccinia prostate specific antigen (rV-PSA) in patients with advanced metastatic prostate cancer was conducted. This report describes 42 patients who were treated with up to three monthly vaccinations.
All patients were entered on a dose-escalation phase I study of recombinant vaccinia containing the gene for PSA (rV-PSA). The primary objective of this study was to determine the safety of this vaccine in metastatic androgen-independent prostate cancer patients. A secondary objective was to assess evidence of anti-tumor activity by PSA measurements, radiologic findings, and immunologic methods.
There was no significant treatment-related toxicity apart from erythema, tenderness, and vesicle formation that lasted several days at the site of injection in some patients. There were immunologic responses, in selected patients, as evidenced by an increase in the proportion of PSA-specific T cells after vaccination. Furthermore, we show that these patients' T cells can lyse PSA-expressing tumor cells in vitro.
Given the low toxicity profile and the evidence of immunologic activity, we believe future study is warranted with PSA-based vaccines in prostate cancer. New PSA-based vaccines and vaccine strategies are currently being evaluated.
The Prostate 11/2002; 53(2):109-17. · 3.48 Impact Factor
ABSTRACT: To determine associations of potentially modifiable nutritional factors with physical and mental health status after adjusting for sociodemographic and comorbid conditions.
Cross-sectional multivariable analysis.
Fifteen dialysis centers across the United States participating in the Reduction of Morbidity and Mortality Among Hemodialysis Patients (HEMO) study.
Enrollment of 1,545 prevalent hemodialysis subjects in the HEMO study. INDEPENDENT (PREDICTOR) VARIABLES: The following nutritional markers were assessed in this analysis: serum albumin, energy intake, protein catabolic rate, serum creatinine, midarm muscle circumference, calf circumference, and smoking status. Smoking status, although not a nutritional factor per se, was also included because it is a modifiable lifestyle factor.
Physical and mental health status were assessed using the medical staff-assessed Karnofsky Index and the patient self-assessed Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36).
After adjusting for sociodemographic factors and comorbid conditions, serum albumin, serum creatinine, and calf circumference were independently associated with Karnofsky Index scores. Similarly, serum creatinine and calf circumference were also independently associated with the Physical Component Summary (PCS) score of the SF-36. Of the nutritional variables selected, no variables were significantly associated with the Mental Component Summary (MCS) score of the SF-36.
Markers of poor nutrition were associated with decreased physical functioning scores, independent of case mix. Measures that improve nutrition may therefore have wide-reaching effects to improve not only morbidity and mortality but also health-related quality of life for patients with end-stage renal disease.
Journal of Renal Nutrition 08/2002; 12(3):160-9. · 1.57 Impact Factor
ABSTRACT: To evaluate the dietary energy intakes (DEI) and dietary protein intakes (DPI) of older (> or = 65 years), middle-aged (50 to 64 years), and younger (< 50 years) maintenance hemodialysis patients enrolled in the Hemodialysis (HEMO) Study, and to describe the relationship between age, nutritional status, functional status, and comorbidity.
A cross-sectional analysis of the first 1,397 participants in baseline (before randomization) was performed.
DEI and DPI, serum albumin, creatinine, total cholesterol, normalized protein catabolic rate (nPCR), equilibrated nPCR (enPCR), functional status, and comorbidities.
Mean DEI, DPI, serum albumin, creatinine, nPCR, and enPCR were significantly lower in the older compared with the younger patients, despite similar doses of dialysis as measured by equilibrated Kt/V. Mean DEI, DPI, nPCR, and enPCR were not significantly different between the middle-aged and older patients, whereas albumin and creatinine were significantly lower in the older patients. Mean dry weight and percent of standard body weight in the younger and older patients were similar. In all groups, mean DEI was lower than both the HEMO study's standard of care (SOC) and the Kidney Disease Outcomes Quality Initiative (K/DOQI) nutrition recommendations, whereas mean DPI was lower than the SOC and K/DOQI recommendations only in the middle-aged and older patients. Middle-aged and older patients had higher cholesterol, lower functional status, and more comorbidities than the younger patients.
Middle-aged and older maintenance dialysis patients may be at greater risk for developing protein-energy malnutrition than their younger counterparts. Inadequate DEI and DPI reported in middle-aged and older patients were associated with lower levels of biomarkers of nutritional status, lower functional status, and higher comorbidities than in the younger patients.
Journal of Renal Nutrition 04/2002; 12(2):87-95. · 1.57 Impact Factor
ABSTRACT: The nutritional status of the first 1,000 patients randomized into the Hemodialysis (HEMO) Study was analyzed at baseline when they received their typical dialysis dose (equilibrated Kt/V = 1.30 +/- 0.22) and dialysis membrane. This is the largest study to date of the nutritional status of chronic hemodialysis patients. The mean (+/- SD) values for these parameters included a serum albumin level of 3.65 +/- 0.38 g/dL, a dietary energy intake of 22.9 +/- 8.4 kcal/kg/day, a dietary protein intake of 0.93 +/- 0.36 g/kg/day, and a double pool normalized protein catabolic rate (enPCR) of 1.00 +/- 0.25 g/kg/day. The percentage of patients below HEMO Study nutritional standards of care included 29% of patients with a serum albumin level less than 3.5 g/dL, 76% of patients with a dietary energy intake less than 28 kcal/kg/day, 61% of patients with a dietary protein intake less than 1.0 g/kg/day, and 52% of patients with an enPCR of less than 1.0 g/kg/day. There was a strong correlation between dietary protein intake and dietary energy intake (r = 0.74, P < 0.0001). Significant correlations were also evident between serum albumin and double pool PCR and between dietary protein intake and double-pool PCR. Kt/V and membrane flux were not predictive of baseline dietary protein intake, dietary energy intake, or serum albumin level. Thus, a majority of patients in the HEMO Study had protein and energy intake levels and enPCR levels that were below National Kidney Foundation Kidney Dialysis Outcome Quality Improvement (NKF-K/DOQI) guidelines.
American Journal of Kidney Diseases 03/2002; 39(2):245-56. · 5.43 Impact Factor
ABSTRACT: An enzyme-linked immunosorbent spot (ELISPOT) assay for interferon γ production has been used to analyze specific T cell
responses to a Flu 9-mer peptide, and a 9-mer peptide of carcinoembryonic antigen (CEA). Assays were performed on peripheral
blood mononuclear cells (PBMC) of HLA-A2-positive patients with CEA-expressing carcinomas, both before and after vaccination
with CEA-based vaccines, and from HLA-A2-positive healthy blood donors. The ELISPOT assay utilized aliquots of frozen PBMC,
and assays were performed after 24 h in culture with peptide to rule out any artifacts due to long-term in vitro stimulation
cycles. An internal standard was used for each assay to define reproducibility of the assay, and all samples from a given
patient (pre- and post-vaccination, with both the Flu and CEA peptides) were analyzed simultaneously. The results indicated
a trend towards healthy blood donors having higher levels of Flu-specific T cell precursors than do colon carcinoma patients,
but these results were not statistically significant (P = 0.06). On the other hand, slightly higher CEA-specific T cell responses were observed in cancer patients with CEA-expressing
carcinomas than in healthy blood donors. PBMC from two CEA-based vaccine clinical trials were analyzed for T cell responses
to the same CEA peptide and to the Flu control peptide. The first trial consisted of three monthly vaccinations of CEA peptide
(designated PPP) in adjuvant. The second trial consisted of cohorts receiving three monthly vaccinations of avipox-CEA recombinant
(designated AAA) or cohorts receiving a primary vaccination with recombinant vaccinia-CEA followed by two monthly vaccinations
with avipox-CEA (designated VAA). Few, if any, CEA-specific T cell responses were seen in the PPP vaccinations, while the
majority of patients receiving the poxvirus CEA recombinants demonstrated increases in CEA-specific T cell responses and no
increases in Flu-specific responses. CEA-specific IgG responses were also demonstrated in patients following recombinant CEA
poxvirus vaccinations. Statistical analyses of the T cell responses to the same CEA peptide demonstrated a P value of 0.028 for the recombinant poxvirus vaccines, as compared with the peptide vaccine. There were no differences seen
(P = 0.37) in Flu-specific responses after these two types of CEA vaccination. These results thus provide the first evidence
that poxvirus recombinant-based vaccines are more potent in the initiation of tumor-antigen-specific T cell responses than
vaccines employing peptide in adjuvant, when assays are conducted in an identical manner, and in defining responses to the
same peptide. These results also demonstrate for the first time that an ELISPOT assay, performed over a 24-h period and without
in vitro sensitization, can be successfully used to monitor immune responses to a tumor-associated antigen in cancer patients.
Cancer Immunology and Immunotherapy 10/2000; 49(10):517-529. · 3.70 Impact Factor