ABSTRACT
PURPOSE: Adults with a history of prostate cancer experience several physical and mental stressors. However, limited information is available about the prevalence of psychological distress in this population and its association with clinical outcomes in a nationally representative sample. METHODS: We identified adults with history of prostate cancer from a nationally representative cohort (2000-2018 US National Health Interview Survey) and its linked mortality files through December 31, 2019. The six-item Kessler Psychological Distress Scale (K6) was used to assess psychological distress. The associations between psychological distress severity, emergency room (ER) usage, and mortality risk were estimated using multivariable logistic and Cox proportional hazards models, which were both adjusted for age, survey year, race/ethnicity, region, education, health insurance, comorbidities, functional limitations, and time since cancer diagnosis. RESULTS: Among the 3,451 adults with history of prostate cancer surveyed, 96 (2.4%), 434 (11.3%), and 2,921 (86.3%) reported severe, moderate, or low/no mental distress, respectively. During the 12 months preceding the survey, 812 (22.8%) adults with history of prostate cancer visited the ER. After a median follow-up of 81 months, 937 (25.5%) deaths occurred. Compared with participants with low/no mental distress, those with severe mental distress reported the highest utilization of the ER (adjusted odds ratio [aOR], 2.57 [95% CI, 1.51 to 4.37]) and exhibited the highest all-cause mortality (adjusted hazard ratio [aHR], 1.83 [95% CI, 1.29 to 2.60]), followed by those with moderate mental distress (ER use aOR, 1.76 [95% CI, 1.29 to 2.42]; all-cause mortality aHR, 1.22 [95% CI, 0.92 to 1.62]). CONCLUSION: Among US adults with history of prostate cancer, psychological distress was associated with increased ER use and mortality risk. Notably, severe psychological distress was correlated with the highest rates of ER visits and mortality risk. However, given the retrospective nature of this study, uncontrolled confounding variables need to be considered when interpreting the findings.
Subject(s)
Prostatic Neoplasms , Psychological Distress , Adult , Male , Humans , Retrospective Studies , Surveys and Questionnaires , Emergency Service, Hospital , Prostatic Neoplasms/complications , Prostatic Neoplasms/epidemiologyABSTRACT
BACKGROUND: Multidisciplinary cancer care (neoadjuvant chemotherapy followed by radical cystectomy or trimodality therapy) is crucial for outcome of muscle-invasive bladder cancer (MIBC), a potentially curable illness. Medicaid expansion through Affordable Care Act (ACA) increased insurance coverage especially among patients of racial minorities. This study aims to investigate the association between Medicaid expansion and racial disparity in timely treatment in MIBC. METHODS: This quasi-experimental study analyzed Black and White individuals aged 18-64 years with stage II and III bladder cancer treated with neoadjuvant chemotherapy followed by radical cystectomy or trimodality therapy from National Cancer Database 2008-2018. Primary outcome was timely treatment started within 45 days following cancer diagnosis. Racial disparity is the percentage-point difference between Black and White patients. Patients in expansion and nonexpansion states were compared using difference-in-differences and difference-in-difference-in-differences analyses, controlling for age, sex, area-level income, clinical stage, comorbidity, metropolitan status, treatment type, and year of diagnosis. RESULTS: The study included 4991 (92.3% White, n = 4605; 7.7% Black, n = 386) patients. Percentage of Black patients who received timely care increased following the ACA in Medicaid expansion states (54.5% pre-ACA vs 57.4% post-ACA) but decreased in nonexpansion states (69.9% pre-ACA vs 53.7% post-ACA). After adjusting covariates, Medicaid expansion was associated with a net 13.7 percentage-point reduction of Black-White patient disparity in timely receipt of MIBC treatment (95% confidence interval = 0.5% to 26.8%; P < .01). CONCLUSIONS: Medicaid expansion was associated with statically significant reduction in racial disparity between Black and White patients in timely multidisciplinary treatment for MIBC.
Subject(s)
Medicaid , Urinary Bladder Neoplasms , United States/epidemiology , Humans , Patient Protection and Affordable Care Act , Urinary Bladder Neoplasms/therapy , Racial Groups , Insurance Coverage , MusclesABSTRACT
The evolving paradigm of the molecular classification of bladder cancer requires models that represent the classifications with less heterogeneity. Robust transcriptome based molecular classifications are essential to address tumor heterogeneity. Patient derived models (PDMs) are a powerful preclinical tool to study specific tumor compartments. We tested if the consensus molecular subtype analysis was applicable to PDMs and evaluated the tumor compartment each model represents. PDMs derived from surgical specimens were established as xenografts (PDX), organoids (PDO), and spheroids (PDS). The surgical specimens and PDMs were molecularly characterized by RNA sequencing. PDMs that were established in immune deficient mice or in vitro significantly downregulated transcripts related to the immune and stromal compartments compared to the surgical specimens. However, PDMs upregulate a patient-specific bladder cancer cell signal which allowed for analysis of cancer cell pathways independent of the tumor microenvironment. Based on transcriptomic signatures, PDMs are more similar to their surgical specimen than the model type; indicating that the PDMs retained unique features of the tumor from which the PDM was derived. When comparing models, PDX models were the most similar to the surgical specimen, while PDO and PDS models were most similar to each other. When the consensus molecular subtype classification system was applied to both the surgical samples and the three PDMs, good concordance was found between all samples indicating that this system of classification can be applied to PDO and PDS models. PDMs reduce tumor heterogeneity and allow analysis of tumor cells while maintaining the gene expression profile representative of the original tumor.
ABSTRACT
BACKGROUND: Local infiltration of CD8(+) T cells (CTLs) in tumor lesions predicts overall clinical outcomes and the clinical benefit of cancer patients from immune checkpoint blockade. In the current study, we evaluated local production of different classes of chemokines in prostate cancer lesions, and the feasibility of their modulation to promote selective entry of CTLs into prostate tumors. METHODS: Chemokine expression in prostate cancer lesion was analyzed by TaqMan-based quantitative PCR, confocal fluorescence microscopy and ELISA. For ex vivo chemokine modulation analysis, prostate tumor explants from patients undergoing primary prostate cancer resections were cultured for 24 hr, in the absence or presence of the combination of poly-I:C, IFNα, and celecoxib (PAC). The numbers of cells producing defined chemokines in the tissues were analyzed by confocal microscopy. Chemotaxis of effector CD8(+) T cells towards the untreated and PAC-treated tumor explant supernatants were evaluated in a standard in vitro migration assays, using 24 well trans-well plates. The number of effector cells that migrated was enumerated by flow cytometry. Pearson (r) correlation was used for analyzing correlations between chemokines and immune filtrate, while paired two tailed students t-test was used for comparison between treatment groups. RESULTS: Prostate tumors showed uniformly low levels of CTL/NK/Th1-recruiting chemokines (CCL5, CXCL9, CXCL10) but expressed high levels of chemokines implicated in the attraction of myeloid derived suppressor cells (MDSC) and regulatory T cells (Treg ): CCL2, CCL22, and CXCL12. Strong positive correlations were observed between CXCL9 and CXCL10 and local CD8 expression. Tumor expression levels of CCL2, CCL22, and CXCL12 were correlated with intratumoral expression of MDSC/Treg markers: FOXP3, CD33, and NCF2. Treatment with PAC suppressed intratumoral production of the Treg -attractant CCL22 and Treg /MDSC-attractant, CXCL12, while increasing the production of the CTL attractant, CXCL10. These changes in local chemokine production were accompanied by the reduced ability of the ex vivo-treated tumors to attract CD4(+) FOXP3(+) Treg cells, and strongly enhanced attraction of the CD8(+) Granzyme B(+) CTLs. CONCLUSIONS: Our data demonstrate that the chemokine environment in prostate cancer can be reprogrammed to selectively enhance the attraction of type-1 effector immune cells and reduce local attraction of MDSCs and Tregs . Prostate 76:1095-1105, 2016. © 2016 Wiley Periodicals, Inc.
Subject(s)
CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/pathology , Cellular Reprogramming Techniques , Immunotherapy/methods , Prostatic Neoplasms/immunology , Prostatic Neoplasms/pathology , Celecoxib/pharmacology , Cellular Reprogramming/immunology , Chemokine CCL2/analysis , Chemokine CCL22/analysis , Chemokine CXCL10/analysis , Chemokine CXCL12/analysis , Chemokine CXCL9/analysis , Chemokines/analysis , Chemotaxis , Cyclooxygenase 2 Inhibitors , Humans , Interferon-alpha/pharmacology , Male , Prostatic Neoplasms/chemistry , T-Lymphocytes, Regulatory/immunologySubject(s)
Anemia, Hemolytic/complications , Erythrocytes/pathology , Liver Failure/complications , Alcoholism/blood , Alcoholism/complications , Alcoholism/pathology , Alcoholism/therapy , Anemia, Hemolytic/blood , Anemia, Hemolytic/pathology , Anemia, Hemolytic/therapy , Erythrocyte Transfusion , Female , Humans , Kidney Failure, Chronic/blood , Kidney Failure, Chronic/etiology , Kidney Failure, Chronic/pathology , Kidney Failure, Chronic/therapy , Liver Cirrhosis, Alcoholic/blood , Liver Cirrhosis, Alcoholic/complications , Liver Cirrhosis, Alcoholic/pathology , Liver Cirrhosis, Alcoholic/therapy , Liver Failure/blood , Liver Failure/pathology , Liver Failure/therapy , Middle Aged , Splenomegaly/blood , Splenomegaly/complications , Splenomegaly/pathology , Splenomegaly/therapyABSTRACT
There is a need for efficacious therapies for metastatic castration-resistant prostate cancer (mCRPC) after disease progression on docetaxel. The SRC tyrosine kinase and its related family members may be important drivers of prostate cancer and can be inhibited by dasatinib. mCRPC patients, after one previous chemotherapy, started dasatinib at 70 mg twice daily, amended to 100 mg daily. The primary endpoint was the disease control (DC) rate, defined as complete response (CR), partial response (PR), or stable disease (SD) in prostate specific antigen (PSA), RECIST, bone scan, and FACT-P score. Up to 41 patients were to be accrued (two-stage design, 21+20) to rule out a null-hypothesized effect of 5 versus 20% (α=0.05, ß=0.1). Secondary endpoints included progression-free survival, toxicity, and pharmacokinetic and pharmacodynamic correlatives. Of 38 patients, 27 were evaluable for response or toxicity. The median duration of therapy was 55 days (6-284). Five patients showed DC after 8 weeks of therapy (18.5% DC, 95% CI: 6.3-38.1%). One PR (3.7% response rate, 95% CI: 0.1-19.0%) was observed in a patient treated for 284 days. Twelve patients (43%) discontinued treatment for toxicity. Dasatinib induced a decrease in phytohemagglutinin-stimulated CSF2, CD40L, GZMB, and IL-2 mRNAs in blood cells, indicating target engagement. Decreases in plasma IL-6 and bone alkaline phosphatase, and in urinary N-telopeptide, were associated with DC. Dasatinib has definite but limited activity in advanced mCRPC, and was poorly tolerated. The observation of a patient with prolonged, objective, clinically significant benefit warrants molecular profiling to select the appropriate patient population.
Subject(s)
Antineoplastic Agents/therapeutic use , Orchiectomy , Prostatic Neoplasms, Castration-Resistant/drug therapy , Prostatic Neoplasms/drug therapy , Protein Kinase Inhibitors/therapeutic use , Pyrimidines/therapeutic use , Thiazoles/therapeutic use , Aged , Aged, 80 and over , Dasatinib , Disease-Free Survival , Humans , Male , Middle Aged , Prostate-Specific Antigen/blood , Prostatic Neoplasms/blood , Prostatic Neoplasms/mortality , Prostatic Neoplasms, Castration-Resistant/blood , Prostatic Neoplasms, Castration-Resistant/mortality , Testosterone/blood , Treatment OutcomeABSTRACT
BACKGROUND: In order to develop improved vaccines for patients with recurrent prostate cancer (PCa), we tested the feasibility of using type-1 polarized dendritic cells (αDC1s) to cross-present antigens from allogeneic PCa cells and to induce functional CD8(+) T cell responses against PCa cells and against defined MHC class I-restricted PCa-relevant epitopes. METHODS: Monocyte-derived DCs from PCa patients were matured using the "standard" cytokine cocktail (IL-1ß/TNFα/IL-6/PGE2) or using the αDC1-polarizing cocktail (IL-1ß/TNFα/IFNα/IFNγ/poly-I:C), loaded with UV-irradiated LNCaP cells, and used to sensitize autologous CD8(+) T cells. RESULTS: αDC1s from PCa patients secreted 10-30 times higher levels of IL-12p70 than sDCs. Importantly this elevated capacity for IL-12p70 secretion was not inhibited by loading with apoptotic tumor cells. Compared to standard DCs, αDC1s induced higher numbers of CD8(+) T cells capable of recognizing both the original PCa cells as well as another PCa cell line, DU145, in MHC class I-restricted fashion. Furthermore, αDC1s induced higher numbers of CD8(+) T cells recognizing defined PCa-specific class I-restricted peptide epitopes of prostate-specific antigen and prostatic acid phosphatase: PAP(135-143) (average 49-fold higher), PAP(112-120) (average 24-fold), PSA(141-150) (average 5.5-fold), and PSA(146-154) (average 11-fold). CONCLUSION: Type-1 polarization of GM-CSF/IL-4-generated DCs enhances their ability to present allogeneic tumor cells and to induce CD8(+) T cells recognizing different PCa cells and multiple defined PCa-specific epitopes. These observations help to develop improved immunotherapies of PCa for patients with different HLA types and lacking autologous tumor material.
Subject(s)
CD8-Positive T-Lymphocytes/immunology , Cancer Vaccines/therapeutic use , Dendritic Cells/immunology , Epitopes, T-Lymphocyte/immunology , Immunotherapy, Adoptive/methods , Prostatic Neoplasms/immunology , Prostatic Neoplasms/therapy , Alkaline Phosphatase/analysis , Cancer Vaccines/immunology , Cell Line, Tumor , Flow Cytometry , Humans , Interleukin-12/biosynthesis , Interleukin-12/immunology , Male , Prostate-Specific Antigen/analysis , Prostatic Neoplasms/blood , Th1 Cells/immunologyABSTRACT
The management of older patients with cancer is historically challenging because of a lack of prospective data regarding the appropriate management of this population. In this review, we address some of the issues and challenges surrounding the treatment of older cancer patients, including the withholding of medically appropriate treatment based on chronologic age, the historical omission of elderly from clinical trials, and the impact of geriatric assessment, and age-related changes in pharmacokinetics and pharmacodynamics. Finally, we conclude by discussing the existing evidence related to cancer treatment in the elderly, focusing primarily on the malignancies most commonly seen in older patients, and making general treatment recommendations where applicable.
Subject(s)
Antineoplastic Agents/pharmacology , Neoplasms/drug therapy , Aged , Clinical Trials as Topic , HumansABSTRACT
PURPOSE: We determined whether thalidomide can prolong progression-free survival in men with biochemically recurrent prostate cancer treated with limited androgen deprivation therapy. MATERIALS AND METHODS: A total of 159 patients were enrolled in a double-blind randomized trial to determine if thalidomide can improve the efficacy of a gonadotropin-releasing hormone agonist in hormone responsive patients with an increasing prostate specific antigen after primary definitive therapy for prostate cancer. Patients were randomized to 6 months of gonadotropin-releasing hormone agonist followed by 200 mg per day oral thalidomide or placebo (oral phase A). At the time of prostate specific antigen progression gonadotropin-releasing hormone agonist was restarted for 6 additional months. Patients were then crossed over to the opposite drug and were treated until prostate specific antigen progression (oral phase B). Testosterone and dihydroxytestosterone were likewise monitored throughout the study. RESULTS: During oral phase A the median time to prostate specific antigen progression was 15 months for the thalidomide group compared to 9.6 months on placebo (p = 0.21). The median time to prostate specific antigen progression during oral phase B for the thalidomide group was 17.1 vs 6.6 months on placebo (p = 0.0002). No differences in time to serum testosterone normalization between the thalidomide and placebo arms were documented during oral phase A and oral phase B. Thalidomide was tolerable although dose reductions occurred in 47% (58 of 124) of patients. CONCLUSIONS: Despite thalidomide having no effect on testosterone normalization, there was a clear effect on prostate specific antigen progression during oral phase B. This is the first study to our knowledge to demonstrate the effects of thalidomide using intermittent hormonal therapy.
Subject(s)
Angiogenesis Inhibitors/administration & dosage , Antineoplastic Agents, Hormonal/therapeutic use , Goserelin/therapeutic use , Leuprolide/therapeutic use , Prostatic Neoplasms/drug therapy , Thalidomide/administration & dosage , Administration, Oral , Aged , Aged, 80 and over , Androgens/physiology , Cross-Over Studies , Double-Blind Method , Humans , Male , Middle AgedABSTRACT
PURPOSE: Groups have investigated time to testosterone recovery in patients who have undergone androgen deprivation therapy, usually by measuring androgen every 3 months, with varying results. To our knowledge this represents the largest study using monthly testosterone and dihydroxytestosterone measurement to evaluate the kinetics of androgen recovery following limited androgen deprivation therapy. MATERIALS AND METHODS: Monthly serum androgen levels were analyzed following 2, 6-month cycles of gonadotropin-releasing hormone agonist therapy as part of a randomized, placebo controlled study of the role of thalidomide in delaying time to prostate specific androgen progression. RESULTS: By the Kaplan-Meier method the median time to testosterone normalization in cycles 1 vs 2 was 15.4 vs 18.3 weeks with similar dihydroxytestosterone recovery times. Neither on-study prostate specific antigen, Gleason score nor thalidomide treatment had a significant impact on time to testosterone normalization. However, in cycle 1 men with low baseline dihydroxytestosterone and those who were more than 67 years old had significantly longer time to T normalization on Cox model analysis. Additionally, in cycle 2 patients with prior local radiation therapy had longer time to testosterone normalization, although this was no longer significant on Cox model analysis. Cox model analysis in cycle 2 showed that low baseline dihydroxytestosterone and testosterone, low testosterone nadir and white race were associated with longer time to testosterone normalization. CONCLUSIONS: Findings of delayed testosterone recovery may be useful for designing and analyzing clinical trials of limited androgen deprivation therapy and for estimating the duration of treatment associated side effects in patients undergoing limited androgen deprivation therapy.
Subject(s)
Androgen Antagonists/therapeutic use , Androgens/blood , Antineoplastic Agents, Hormonal/therapeutic use , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/pathology , Testosterone/blood , Aged , Aged, 80 and over , Androgens/metabolism , Biopsy, Needle , Dose-Response Relationship, Drug , Drug Administration Schedule , Follow-Up Studies , Goserelin/therapeutic use , Humans , Immunohistochemistry , Leuprolide/therapeutic use , Male , Middle Aged , Neoplasm Staging , Probability , Prospective Studies , Prostate-Specific Antigen/blood , Recovery of Function , Reference Values , Risk Assessment , Testosterone/metabolism , Thalidomide/therapeutic use , Treatment OutcomeABSTRACT
BACKGROUND: 17-Allylamino-17-demethoxygeldanamycin (17-AAG) inhibits heat shock protein 90, promotes degradation of oncoproteins, and exhibits synergy with paclitaxel in vitro. We conducted a phase I study in patients with advanced malignancies to determine the recommended phase II dose of the combination of 17-AAG and paclitaxel. METHODS: Patients with advanced solid malignancies that were refractory to proven therapy or without any standard treatment were included. 17-AAG (80-225 mg/m2) was given on days 1, 4, 8, 11, 15, and 18 of each 4-week cycle to sequential cohorts of patients. Paclitaxel (80-100 mg/m2) was administered on days 1, 8, and 15. Pharmacokinetic studies were conducted during cycle 1. RESULTS: Twenty-five patients were accrued to five dose levels. The median number of cycles was 2. Chest pain (grade 3), myalgia (grade 3), and fatigue (grade 3) were dose-limiting toxicities at dose level 4 (225 mg/m2 17-AAG and 80 mg/m2 paclitaxel). None of the six patients treated at dose level 3 with 17-AAG (175 mg/m2) and paclitaxel (80 mg/m2) experienced dose-limiting toxicity. Disease stabilization was noted in six patients, but there were no partial or complete responses. The ratio of paclitaxel area under the concentration to time curve when given alone versus in combination with 17-AAG was 0.97 +/- 0.20. The ratio of end-of-infusion concentration of 17-AAG (alone versus in combination with paclitaxel) was 1.14 +/- 0.51. CONCLUSIONS: The recommended phase II dose of twice-weekly 17-AAG (175 mg/m2) and weekly paclitaxel (80 mg/m2/wk) was tolerated well. There was no evidence of drug-drug pharmacokinetic interactions.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Neoplasms/drug therapy , Adult , Aged , Area Under Curve , Benzoquinones/administration & dosage , Benzoquinones/adverse effects , Benzoquinones/pharmacokinetics , Drug Administration Schedule , Drug Interactions , Female , Humans , Lactams, Macrocyclic/administration & dosage , Lactams, Macrocyclic/adverse effects , Lactams, Macrocyclic/pharmacokinetics , Male , Maximum Tolerated Dose , Middle Aged , Paclitaxel/administration & dosage , Paclitaxel/adverse effects , Paclitaxel/pharmacokineticsABSTRACT
BACKGROUND: Survival in patients with metastatic, chemotherapy-naive, androgen-independent prostate cancer (AIPC) is improved with 10 to 12 cycles of docetaxel-containing chemotherapy but further management is undefined. In the current study, the authors examined retreatment with the same regimen after a treatment holiday. METHODS: Patients treated with docetaxel at a dose of 36 mg/m(2) plus either high-dose calcitriol (DN-101; 45 mug) or placebo administered weekly for 3 of every 4 weeks could suspend treatment if their serum prostate-specific antigen (PSA) level was reduced >or=50% and reached a level
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Calcitriol/administration & dosage , Prostatic Neoplasms/drug therapy , Taxoids/administration & dosage , Aged , Aged, 80 and over , Docetaxel , Double-Blind Method , Humans , Male , Middle Aged , Prostate-Specific Antigen/bloodABSTRACT
Dysbalanced production of inflammatory cytokines is involved in immunosenescence in aging. The age-related changes of the levels of circulating inflammatory mediators and their clinical importance have not been investigated until recently. Still, little is known about the influence of aging on circulating levels of many cytokines, chemokines, growth factors, and angiogenic factors. In the present study, we evaluated the effect of aging on 30 different serum biomarkers involved in pro- and anti-inflammatory responses using multianalyte LabMAP Luminex technology. The simultaneous measurement of serological markers has been done in 397 healthy subjects between 40 and 80 years old. We demonstrated an increase in serum interferon-gamma-inducible chemokines (MIG and IP-10), eotaxin, chemoattractant for eosinophils, and soluble TNFR-II with advancing age. Serum levels of EGFR and EGF, important regulators of cell growth and differentiation, were decreased with age in healthy donors. These data suggest novel pathways, which may be involved in age-associated immunosenescence.
Subject(s)
Aging , Biomarkers/blood , Adult , Age Distribution , Aged , Aged, 80 and over , Chemokine CCL11/blood , Chemokine CXCL10/blood , Chemokine CXCL9/blood , Epidermal Growth Factor/blood , ErbB Receptors/blood , Female , Humans , Male , Middle Aged , Receptors, Tumor Necrosis Factor, Type II/blood , Reference Values , SolubilityABSTRACT
Tumor produces a number of immunosuppressive factors that block maturation of dendritic cells (DCs). Here, we demonstrated that endogenous factors presented in the serum of patients with prostate cancer (CaP) inhibited the generation of functionally active DCs from CD14+ monocytes in vitro. We have shown a significant inhibitory potential of serum obtained from patients with CaP and benign prostate hyperplasia benign prostatic hyperplasia (BPH) when compared with serum from healthy volunteers. As assessed by flow cytometry, expression of CD83, CD86, and CD40 molecules was strongly inhibited by CaP and BPH serum. In addition, these DCs were weak stimulators of allogeneic T cell proliferation when compared with DCs produced in the presence of healthy volunteer serum. Statistical analysis of the results revealed a positive relationship between the inhibition of expression of DC markers CD83 and CD80 and the levels of serum-free prostate-specific antigen (PSA). These data suggest that the DC system may be impaired in CaP patients.
Subject(s)
Dendritic Cells/cytology , Dendritic Cells/immunology , Prostate-Specific Antigen/biosynthesis , Prostatic Neoplasms/blood , Prostatic Neoplasms/immunology , Antigens, CD/biosynthesis , B7-2 Antigen/biosynthesis , CD40 Antigens/biosynthesis , Case-Control Studies , Cell Proliferation , Flow Cytometry , Humans , Immunoglobulins/biosynthesis , Immunosuppressive Agents/pharmacology , Lipopolysaccharide Receptors/biosynthesis , Male , Membrane Glycoproteins/biosynthesis , Models, Statistical , Prognosis , Prostatic Neoplasms/diagnosis , CD83 AntigenABSTRACT
PURPOSE: We investigated the safety and efficacy (response rates, time to disease progression, survival) of trastuzumab, carboplatin, gemcitabine, and paclitaxel in advanced urothelial carcinoma patients and prospectively evaluated human epidermal growth factor receptor-2 (Her-2/neu) overexpression rates. PATIENTS AND METHODS: Advanced urothelial carcinoma patients were screened for Her-2/neu overexpression. Eligibility for therapy required human epidermal growth factor receptor-2 (Her-2/neu) overexpression by immunohistochemistry (IHC), gene amplification and/or elevated serum Her-2/neu, no prior chemotherapy for metastasis, and adequate organ function including a normal cardiac function. Treatment consisted of trastuzumab (T) 4 mg/kg loading dose followed by 2 mg/kg on days 1, 8, and 15; paclitaxel (P) 200 mg/m2 on day 1; carboplatin (C; area under the curve, 5) on day 1; and gemcitabine (G) 800 mg/m2 on days 1 and 8. The primary end point was cardiac toxicity. RESULTS: Fifty-seven (52.3%) of 109 registered patients were Her-2/neu positive, and 48.6% were positive by IHC. Her-2/neu-positive patients had more metastatic sites and visceral metastasis than did Her-2/neu negative patients. Forty-four of 57 Her-2/neu-positive patients were treated with TPCG. The median number of cycles was six (range, 1 to 12 cycles). The most common grade 3/4 toxicity was myelosuppression. Grade 3 sensory neuropathy occurred in 14% of patients, and 22.7% experienced grade 1 to 3 cardiac toxicity (grade 3, n = 2: one left ventricular dysfunction, one tachycardia). There were three [corrected] therapy-related deaths. Thirty-one (70%) of 44 patients responded (five complete and 26 partial), and 25 (57%) of 44 were confirmed responses. Median time to progression and survival were 9.3 and 14.1 months, respectively. CONCLUSION: We prospectively characterized Her-2/neu status in advanced urothelial carcinoma patients. TPCG is feasible; cardiac toxicity rates were higher than projected, but the majority were grade two or lower. Determining the true contribution of trastuzumab requires a randomized trial.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , ErbB Receptors/analysis , Receptor, ErbB-2/analysis , Urinary Bladder Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal, Humanized , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carboplatin/administration & dosage , Deoxycytidine/administration & dosage , Deoxycytidine/analogs & derivatives , Female , Humans , Immunohistochemistry , Male , Middle Aged , Paclitaxel/administration & dosage , Prospective Studies , Trastuzumab , Urinary Bladder Neoplasms/chemistry , Urinary Bladder Neoplasms/mortality , GemcitabineABSTRACT
The immune system shows a decline in responsiveness to antigens both with aging, as well as in the presence of tumors. The malfunction of the immune system with age can be attributed to developmental and functional alterations in several cell populations. Previous studies have shown defects in humoral responses and abnormalities in T cell function in aged individuals, but have not distinguished between abnormalities in antigen presentation and intrinsic T cell or B cell defects in aged individuals. Dendritic cells (DC) play a pivotal role in regulating immune responses by presenting antigens to naïve T lymphocytes, modulating Th1/Th2/Th3/Treg balance, producing numerous regulatory cytokines and chemokines, and modifying survival of immune effectors. DC are receiving increased attention due to their involvement in the immunobiology of tolerance and autoimmunity, as well as their potential role as biological adjuvants in tumor vaccines. Recent advances in the molecular and cell biology of different DC populations allow for addressing the issue of DC and aging both in rodents and humans. Since DC play a crucial role in initiating and regulating immune responses, it is reasonable to hypothesize that they are directly involved in altered antitumor immunity in aging. However, the results of studies focusing on DC in the elderly are conflicting. The present review summarizes the available human and experimental animal data on quantitative and qualitative alterations of DC in aging and discusses the potential role of the DC system in the increased incidence of cancer in the elderly.
Subject(s)
Aging/physiology , Dendritic Cells/cytology , Neoplasms/immunology , Aging/immunology , Animals , Cell Count , Dendritic Cells/immunology , Dendritic Cells/physiology , Humans , Immune System/cytology , Immune System/physiologyABSTRACT
PURPOSE: Patients with adverse pathological features are at high risk for recurrence following radical prostatectomy. To improve outcomes in this population we performed a phase II study of adjuvant docetaxel in these high risk patients. MATERIALS AND METHODS: Patients with nonmetastatic radical prostatectomy at greater than 50% risk for recurrence by 3 years were eligible. Pathological findings were centrally reviewed and risk assessment was based on a validated multivariate Cox proportional hazards model. Treatment consisted of 6 cycles of 35 mg/m(2) docetaxel weekly given 4 to 12 weeks following surgery. Progression was defined as a prostate specific antigen of 0.4 ng/ml or greater, radiological/pathological evidence of recurrent disease or death from any cause. To screen for the potential benefit of adjuvant weekly docetaxel we used nomogram predicted progression-free survival as a historical control. RESULTS: A total of 77 patients were registered between April 2002 and January 2004. Two patients had grade IV hyperglycemia and 20 had grade III toxicity. At a median followup of 29.2 months (range 1.6 to 39.2) 46 of 76 evaluable cases (60.5%) progressed. Observed median progression-free survival was 15.7 months (95% CI 12.8-25.1). Predicted median progression-free survival in a matched population was 10 months. Seven patients died, including 4 of prostate cancer, 1 with intra-abdominal bleeding during treatment and 2 of pneumonia and sudden cardiac death, respectively, following treatment. CONCLUSIONS: Adjuvant docetaxel for prostate cancer is feasible with significant reversible but acceptable toxicity. The actual median progression-free survival of 15.7 months was longer than the nomogram predicted rate for this patient population. Adjuvant docetaxel treatment should be further evaluated in phase III trials in patients with high risk prostate cancer.
Subject(s)
Antineoplastic Agents/therapeutic use , Neoplasm Recurrence, Local/prevention & control , Prostatectomy , Prostatic Neoplasms/therapy , Taxoids/therapeutic use , Adult , Aged , Antineoplastic Agents/administration & dosage , Biomarkers, Tumor/blood , Chemotherapy, Adjuvant , Disease-Free Survival , Docetaxel , Drug Administration Schedule , Follow-Up Studies , Humans , Male , Middle Aged , Neoplasm Recurrence, Local/blood , Neoplasm Recurrence, Local/mortality , Pilot Projects , Prospective Studies , Prostate-Specific Antigen/blood , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/mortality , Prostatic Neoplasms/surgery , Radiation-Sensitizing Agents , Risk Factors , Survival Rate/trends , Taxoids/administration & dosage , Treatment OutcomeABSTRACT
PURPOSE: To compare the safety and activity of DN-101, a new high-dose oral formulation of calcitriol designed for cancer therapy, and docetaxel with placebo and docetaxel. PATIENTS AND METHODS: Patients with progressive metastatic androgen-independent prostate cancer and adequate organ function received weekly docetaxel 36 mg/m2 intravenously for 3 weeks of a 4-week cycle combined with either 45 microg DN-101 or placebo taken orally 1 day before docetaxel. The primary end point was prostate-specific antigen (PSA) response within 6 months of enrollment, defined as a 50% reduction confirmed at least 4 weeks later. RESULTS: Two hundred fifty patients were randomly assigned. Baseline characteristics were similar in both arms. Within 6 months, PSA responses were seen in 58% in DN-101 patients and 49% in placebo patients (P = .16). Overall, PSA response rates were 63% (DN-101) and 52% (placebo), P = .07. Patients in the DN-101 group had a hazard ratio for death of 0.67 (P = .04) in a multivariate analysis that included baseline hemoglobin and performance status. Median survival has not been reached for the DN-101 arm and is estimated to be 24.5 months using the hazard ratio, compared with 16.4 months for placebo. Grade 3/4 adverse events occurred in 58% of DN-101 patients and in 70% of placebo-treated patients (P = .07). Most common grade 3/4 toxicities for DN-101 versus placebo were neutropenia (10% v 8%), fatigue (8% v 16%), infection (8% v 13%), and hyperglycemia (6% v 12%). CONCLUSION: This study suggests that DN-101 treatment was associated with improved survival, but this will require confirmation because survival was not a primary end point. The addition of weekly DN-101 did not increase the toxicity of weekly docetaxel.
Subject(s)
Androgens/metabolism , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Calcitriol/administration & dosage , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/mortality , Taxoids/administration & dosage , Age Factors , Aged , Biopsy, Needle , Calcitriol/adverse effects , Docetaxel , Dose-Response Relationship, Drug , Double-Blind Method , Drug Administration Schedule , Follow-Up Studies , Humans , Male , Middle Aged , Neoplasm Staging , Placebos/administration & dosage , Prostate-Specific Antigen/blood , Prostatic Neoplasms/pathology , Risk Assessment , Survival Rate , Taxoids/adverse effects , Treatment OutcomeABSTRACT
We have recently reported that MHC class I Ag-processing machinery (APM) component expression in dendritic cells (DC) might be down-regulated by tumor cells. However, the tumor-derived factors responsible for inhibition of the APM component expression in DC generated in the tumor microenvironment as well as potential protective mechanism have not yet been investigated. In this article, we demonstrate that expression of several MHC class I APM components, including MB1 (beta5), LMP2, LMP7, LMP10, and ERp57, is significantly down-regulated in human DC generated in the presence of primary oral squamous cell carcinoma cell lines or coincubated with purified gangliosides. Suppression of MHC class I APM component expression in DC generated in the presence of tumor cells was significantly attenuated by the inhibition of glucosyl transferase in tumor cells, suggesting that tumor-induced MHC class I APM component down-regulation in DC was mediated in part by oral squamous cell carcinoma-derived gangliosides. Furthermore, rIL-15 restored both tumor cell-induced and ganglioside-induced MHC class I APM component expression in DC, as well as their ability to present Ags to autologous Ag-specific T cells. These results demonstrate that IL-15 restores MHC class I APM component expression in DC down-regulated by tumor-derived gangliosides.
Subject(s)
Antigen Presentation , Carcinoma, Squamous Cell/immunology , Dendritic Cells/physiology , Gangliosides/physiology , Histocompatibility Antigens Class I/metabolism , Interleukin-15/pharmacology , Mouth Neoplasms/immunology , Cell Line, Tumor , Humans , Ovalbumin/immunology , RNA, Small Interfering/pharmacologyABSTRACT
Breast and kidney-expressed chemokine (BRAK) CXCL14 is a new CXC chemokine with unknown function and receptor selectivity. The majority of head and neck squamous cell carcinoma (HNSCC) and some cervical squamous cell carcinoma do not express CXCL14 mRNA, as opposed to constitutive expression by normal oral squamous epithelium. In this study, we demonstrate that the loss of CXCL14 in HNSCC cells and at HNSCC primary tumor sites was correlated with low or no attraction of dendritic cell (DC) in vitro, and decreased infiltration of HNSCC mass by DC at the tumor site in vivo. Next, we found that recombinant human CXCL14 and CXCL14-positive HNSCC cell lines induced DC attraction in vitro, whereas CXCL14-negative HNSCC cells did not chemoattract DC. Transduction of CXCL14-negative HNSCC cell lines with the human CXCL14 gene resulted in stimulation of DC attraction in vitro and increased tumor infiltration by DC in vivo in chimeric animal models. Furthermore, evaluating the biologic effect of CXCL14 on DC, we demonstrated that the addition of recombinant human CXCL14 to DC cultures resulted in up-regulation of the expression of DC maturation markers, as well as enhanced proliferation of allogeneic T cells in MLR. Activation of DC with recombinant human CXCL14 was accompanied by up-regulation of NF-kappaB activity. These data suggest that CXCL14 is a potent chemoattractant and activator of DC and might be involved in DC homing in vivo.