Patient Engagement by the Tobacco Quitline After Electronic Referrals.

INTRODUCTION: Referrals through the electronic health record (EHR) system provide an efficient evidence-based method to connect patients to the Tobacco Quitline. However, patients frequently do not respond to Quitline phone calls or accept services. The goal of this study was to characterize factors associated with successful engagement with Quitline following e-referrals by physicians in Maryland. AIMS AND METHODS: This is a cross-sectional study with hierarchical data modeling. Data for 1790 patients e-referred in 2018-2019 by the University of Maryland Medical System (UMMS) were analyzed. Patients' engagement was assessed using a generalized estimating equation multivariable regression model for ordinal outcomes at two levels: Picking up a phone call from Quitline (1-800-QUIT-NOW) and enrollment in tobacco cessation programs. RESULTS: Older age, female gender, black race, low socioeconomic status, and provider's skills were significantly associated with successful outcomes of Quitline referral. The engagement with Quitline was higher in black non-Hispanic patients compared to other racial/ethnic groups (phone call response odds ratio [OR] = 1.99, 95% confidence interval [CI] = 1.35% to 2.93% and service acceptance OR = 1.89, 95% CI = 1.28% to 2.79%). Patients residing in socioeconomically deprived areas were more likely to respond to Quitline phone calls compared to those from affluent neighborhoods (OR = 1.52, 95% CI = 1.03% to 2.25%). Patients referred by faculty or attending physicians were more likely to respond compared to those referred by residents (OR = 1.23, 95% CI 1.04, 1.44, p = .0141). CONCLUSIONS: Multiple factors impact successful engagement with Quitline. Additional means to improve Quitline engagement success may include focused messaging on tobacco cessation benefits to patients, and skillful counseling by the provider. IMPLICATIONS: Implementation of the clinical decision support (CDS) tool for electronic referrals to the Tobacco Quitline at the UMMS was successful in providing evidence-based free service to elderly patients and socioeconomically disadvantaged racial and ethnic minorities. The CDS also served to engage physicians in conversation about tobacco use and cessation with every tobacco-using patient. Curricular content for physicians in training should be enriched to expand tobacco use and treatment.

Text Messaging as a Communication Modality to Promote Screening Mammography in Low-income African American Women.

INTRODUCTION: Though text messages are increasingly used in health promotion, the current understanding of text message-based interventions to increase screening mammography in low-income African American women is limited. This study aimed to assess the feasibility and acceptability of a text message-based intervention to increase screening mammography in low-income African American women. MATERIALS AND METHODS: A 15-item, self-administered, paper-based survey on cell phone ownership, text messaging practices and preferences for future breast health information was administered to 120 female patients at an urban family medicine office. Descriptive analyses and demographic correlates of text messaging practices and preferences were examined. RESULTS AND DISCUSSION: The majority of respondents (95%) were cell phone owners of whom 81% reported texting. Prior receipt of a text message from a doctor's office was reported by 51% of cell phone owners. Mammography appointment reminders were the most desired content for future breast health text messages. Age (≥ 70 years old) was found to have a significant negative relationship with text messaging practices and perceptions. IMPLICATIONS: The use of text messages to promote mammography was found to be acceptable in this patient population. In addition to age, variables such as the frequency, timing and subject content of text messages also influence their acceptability.

Association of COVID-19 With Race and Socioeconomic Factors in Family Medicine.

INTRODUCTION: Recent data demonstrated that socioeconomic, environmental, demographic, and health factors can contribute to vulnerability for coronavirus 2019 (COVID-19). The goal of this study was to assess association between severe acute respiratory syndrome coronavirus (SARS CoV-2) infection and demographic and socioeconomic factors in patients from a large academic family medicine practice to support practice operations. METHODS: Patients referred for SARS CoV-2 testing by practice providers were identified using shared patient lists in the electronic health records (Epic). The Health Information Exchange (CRISP) was used to identify additional practice-attributed patients receiving testing elsewhere. RESULTS: Compared with white non-Hispanic patients, the odds of COVID-19 detection were higher in black non-Hispanic (odds ratio [OR] = 1.75; 95% CI, 1.18-2.59, P = .0052) and Hispanic patients (OR = 5.40; 95% CI, 3.11-9.38, P < .0001). The latent class analysis revealed additional patterns in health disparities. Patients living in the areas with Area Deprivation Index 8-10 who were predominantly black had higher risk for SARS CoV-2 infection compared with patients living in less socioeconomically deprived areas who were predominantly white (OR = 1.68; 95% CI, 1.25-2.28; P = .0007). CONCLUSION: Our data provide insight into the association of COVID-19 with race/ethnic minority patients residing in highly socioeconomically deprived areas. These data could impact outreach and management of ambulatory COVID-19 in the future.

The effect of a primary care-based Medical Weight Loss Program on weight loss and anthropomorphic metrics.

BACKGROUND: Diet and lifestyle intervention programs have been shown to be effective in decreasing obesity/overweight and many associated comorbidities in specialty research settings. There is very little information however as to the efficacy of such programs conducted in usual/typical primary care practices. We analysed effectiveness of the Medical Weight Loss Program (MWLP) designed to specifically address overweight/obesity in the setting of an urban academic primary care practice. OBJECTIVE: To determine whether participation in the MWLP within a general primary care setting can result in weight loss. METHODS: A retrospective medical chart review of patients treated in MWLP and a control group of patients with obesity receiving regular care in the general primary care setting. From the practice database (1 April 2015-31 March 2016), 209 patients (≥18 years old) who participated in the MWLP were identified; 265 controls were selected from the remaining population based on the presence of the obesity-related diagnoses. RESULTS: MWLP patients lost on average 2.35 ± 5.88 kg in 6 months compared to their baseline weight (P < 0.0001). In contrast, the control group demonstrated a trend of gaining on average 0.37 ± 6.03 kg. Having three or more visits with the MWLP provider within 6 months after program initiation was the most important factor associated with successful loss of at least 5% of the baseline weight. Weight loss also correlated with a decrease in abdominal girth. CONCLUSION: MWLP integrated into the general primary care practice may potentially be an effective model for managing obesity and related morbidities.

Utilizing the Learning Health System Adaptation to guide Family Medicine Practice to COVID-19 response.

COVID-19 supportive quarantine care in the community is managed by primary care practices. There is no current guidance on how a primary care practice with high volumes of patients screened for COVID-19 can re-configure itself to become responsive to the pandemic. We examined Learning Health System guidance from the National Academies of Science, Engineering and Medicine and adapted it to our primary care practice to create an efficient, effective, adaptive response to the COVID-19 pandemic. We suggest evaluating this response in the future for effectiveness and efficiency.

Outcomes of a Community-based Breast Cancer Screening Program in Baltimore City.

INTRODUCTION: African American women have disproportionately high breast cancer (BC) mortality in comparison with White women. Early BC detection rates are lower in African American women than White women, reflecting sub-optimal use of screening mammography particularly among women who are uninsured. METHODS: A descriptive analysis of a community-based, cancer control program targeted at uninsured African Americans is presented. Program outcomes and correlates of program retention and BC detection are summarized. RESULTS: Data for 5,669 enrollees and 10,357 mammograms were analyzed. Breast cancer was diagnosed in 113 women, 69% at an early stage. The majority (72%) of BC cases were diagnosed during the initial program cycle. The strongest correlates of program retention were non-Hispanic ethnicity and prior mammography (p<.0001). DISCUSSION: This community-based cancer control program provided an early BC detection benefit to enrollees regardless of whether program services were conducted for only one cycle or were continued at regular intervals.

A Statewide Analysis of the Incidence and Outcomes of Acute Mesenteric Ischemia in Maryland from 2009 to 2013.

INTRODUCTION: Acute mesenteric ischemia is a surgical emergency that entails complex, multi-modal management, but its epidemiology and outcomes remain poorly defined. The aim of this study was to perform a population analysis of the contemporary incidence and outcomes of mesenteric ischemia. METHODS: This was a retrospective analysis of acute mesenteric ischemia in the state of Maryland during 2009-2013 using a comprehensive statewide hospital admission database. Demographics, illness severity, comorbidities, and outcomes were studied. The primary outcome was inpatient mortality. Survivors and non-survivors were compared using univariate analyses, and multivariable logistic regression analysis was performed to evaluate risk factors for mortality. RESULTS: During the 5-year study period, there were 3,157,499 adult hospital admissions in Maryland. A total of 2,255 patients (0.07%) had acute mesenteric ischemia, yielding an annual admission rate of 10/100,000. Increasing age, hypercoagulability, cardiac dysrhythmia, renal insufficiency, increasing illness severity, and tertiary hospital admission were associated with development of mesenteric ischemia. Inpatient mortality was high (24%). After multivariate analysis, independent risk factors for death were age >65 years, critical illness severity, mechanical ventilation, tertiary hospital admission, hypercoagulability, renal insufficiency, and dysrhythmia. CONCLUSION: Acute mesenteric ischemia occurs in approximately 1/1,000 admissions in Maryland. Patients with mesenteric ischemia have significant illness severity, substantial rates of organ dysfunction, and high mortality. Patients with chronic comorbidities and acute organ dysfunction are at increased risk of death, and recognition of these risk factors may enable prevention or earlier control of mesenteric ischemia in high-risk patients.

Acute Care Surgery: Defining the Economic Burden of Emergency General Surgery.

BACKGROUND: Trauma centers (TCs) have been shown to provide lifesaving, but more expensive, care when compared with non-TCs (NTC). Limited data exist about the economic impact of emergency general surgery (EGS) patients on health care systems. We hypothesized that the economic burden would be higher for EGS patients managed at TCs vs NTCs. METHODS: The Maryland Health Services Cost Review Commission database was queried from 2009 to 2013. The American Association for the Surgery of Trauma EGS ICD-9 codes were used to define the top 10 EGS diagnoses. Demographic characteristics, TC designation, severity of illness, and hospital charge data were collected. Differences in total charges between TCs and NTCs were analyzed by Wilcoxon test using SAS 9.3 software (SAS Institute). RESULTS: A total of 435,623 patients were included. Median age was 61 years (interquartile range 47 to 76 years) and 55.9% were female. Median length of stay was 4 days; 90.3% were admitted via emergency department; and overall mortality was 5.1%. Overall median charges were $11,081 for TC vs $8,264 for NTC (p < 0.0001). Minor, moderate, major, and extreme severities of illness all had higher charges at TC vs NTC with no ICU admissions, respectfully ($5,908 vs $5,243; $7,051 vs $6,003; $10,501 vs $8,777; and $23, 997 vs $18,381; p < 0.001). Care at TCs was nearly twice as expensive if patients were admitted to the ICU, even when stratifying by severity of illness. CONCLUSIONS: Emergency general surgery patients treated at TCs incurred increased costs compared with NTCs, independent of patient severity. These costs nearly doubled for those admitted to the ICU. As acute care surgery grows as a specialty, additional investigation is required to better understand the reasons for this cost differential.

Emergency General Surgery: Defining Burden of Disease in the State of Maryland.

Acute care surgery services continue expanding to provide emergency general surgery (EGS) care. The aim of this study is to define the characteristics of the EGS population in Maryland. Retrospective review of the Health Services Cost Review Commission database from 2009 to 2013 was performed. American Association for the Surgery of Trauma-defined EGS ICD-9 codes were used to define the EGS population. Data collected included patient demographics, admission origin [emergency department (ED) versus non-ED], length of stay (LOS), mortality, and disposition. There were 3,157,646 encounters. In all, 817,942 (26%) were EGS encounters, with 76 per cent admitted via an ED. The median age of ED patients that died was 74 years versus 61 years for those that lived (P < 0.001). Twenty one per cent of ED admitted patients had a LOS > 7 days. Of 78,065 non-ED admitted patients, the median age of those that died was 68 years versus 59 years for those that lived (P < 0.001). Twenty eight per cent of non-ED admits had LOS > 7 days. In both ED and non-ED patients, there was a bimodal distribution of death, with most patients dying at LOS ≤ 2 or LOS > 7 days. In this study, EGS diagnoses are present in 26 per cent of inpatient encounters in Maryland. The EGS population is elderly with prolonged LOS and a bimodal distribution of death.

Immunostimulatory early phenotype of tumor-associated macrophages does not predict tumor growth outcome in an HLA-DR mouse model of prostate cancer.

Tumor-associated macrophages (TAM) were shown to support the progression of many solid tumors. However, anti-tumor properties of TAM were also reported in several types of cancer. Here, we investigated the phenotype and functions of TAM in two transgenic mouse models of prostate cancer that display striking differences in tumor growth outcome. Mice expressing prostate-specific antigen (PSA) as a self-antigen specifically in prostate (PSAtg mice) rejected PSA-expressing transgenic adenocarcinoma of mouse prostate (TRAMP) tumors. However, the introduction of HLA-DRB1*1501 (DR2b) transgene presenting PSA-derived peptides in a MHC class II-restricted manner exacerbated the growth of TRAMP-PSA tumors in DR2bxPSA F 1 mice. Despite the difference in tumor growth outcome, tumors in both strains were equally and intensively infiltrated by macrophages on the first week after tumor challenge. TAM exhibited mixed M1/M2 polarization and simultaneously produced pro-inflammatory (TNFα, IL1ß) and anti-inflammatory (IL10) cytokines. TAM from both mouse strains demonstrated antigen-presenting potential and pronounced immunostimulatory activity. Moreover, they equally induced apoptosis of tumor cells. In vivo depletion of macrophages in DR2bxPSA F 1 but not PSAtg mice aggravated tumor growth suggesting that macrophages more strongly contribute to anti-tumor immunity when specific presentation of PSA to CD4+ T cells is possible. In summary, we conclude that in the early stages of tumor progression, the phenotype and functional properties of TAM did not predict tumor growth outcome in two transgenic prostate cancer models. Furthermore, we demonstrated that during the initial stage of prostate cancer development, TAM have the potential to activate T cell immunity and mediate anti-tumor effects.

Association of obesity and sleep problems among breast cancer survivors: results from a registry-based survey study.

PURPOSE: Sleep-related complaints are common among breast cancer survivors. However, the risk factors underlying sleep disturbances in this population are not completely understood. Some studies have shown that maintaining normal weight can result in a reduced risk of cancer-related symptoms, including sleep problems; however, data from published studies are not consistent. This study examined the associations between body mass index (BMI) and sleep-related complaints in breast cancer survivors. METHODS: Self-reported survey data from 861 breast cancer survivors at a single institution were analyzed. BMI was calculated based on self-reported weight and height at the time of the survey. Daytime sleepiness was assessed using the Epworth Sleepiness Scale. Average sleep duration was calculated based on the reported hours of sleep on a typical weekday and weekend. Associations between BMI and the sleep outcomes were estimated using multivariable logistic regression. RESULTS: In adjusted models, BMI was not significantly associated with either excessive daytime sleepiness or "short" sleep pattern (≤ 6 h) in our sample of breast cancer survivors. Younger age, presence of strong acute pain, and lower level of education were independent risk factors for excessive daytime sleepiness. African American race, presence of strong acute pain, and lower level of education were independent risk factors for being a short sleeper. CONCLUSIONS: Findings from this study indicate that BMI is not independently associated with sleep-related outcomes among breast cancer survivors. More research is needed to identify cancer survivors who are at increased risk for sleep disturbances as well as the mechanisms that underlie such disturbances.

Acute care surgery: defining mortality in emergency general surgery in the state of Maryland.

BACKGROUND: Emergency general surgery (EGS) is a major component of acute care surgery, however, limited data exist on mortality with respect to trauma center (TC) designation. We hypothesized that mortality would be lower for EGS patients treated at a TC vs non-TC (NTC). STUDY DESIGN: A retrospective review of the Maryland Health Services Cost Review Commission database from 2009 to 2013 was performed. The American Association for the Surgery of Trauma EGS ICD-9 codes were used to identify EGS patients. Data collected included demographics, TC designation, emergency department admissions, and All Patients Refined Severity of Illness (APR_SOI). Trauma center designation was used as a marker of a formal acute care surgery program. Primary outcomes included in-hospital mortality. Multivariable logistic regression analysis was performed controlling for age. RESULTS: There were 817,942 EGS encounters. Mean ± SD age of patients was 60.1 ± 18.7 years, 46.5% were males; 71.1% of encounters were at NTCs; and 75.8% were emergency department admissions. Overall mortality was 4.05%. Mortality was calculated based on TC designation controlling for age across APR_SOI strata. Multivariable logistic regression analysis did not show statistically significant differences in mortality between hospital levels for minor APR_SOI. For moderate APR_SOI, mortality was significantly lower for TCs compared with NTCs (p < 0.001). Among TCs, the effect was strongest for Level I TC (odds ratio = 0.34). For extreme APR_SOI, mortality was higher at TCs vs NTCs (p < 0.001). CONCLUSIONS: Emergency general surgery patients treated at TCs had lower mortality for moderate APR_SOI, but increased mortality for extreme APR_SOI when compared with NTCs. Additional investigation is required to better evaluate this unexpected finding.

Breaking immune tolerance by targeting CD25+ regulatory T cells is essential for the anti-tumor effect of the CTLA-4 blockade in an HLA-DR transgenic mouse model of prostate cancer.

INTRODUCTION: Recent studies suggest that the cancer immunotherapy based on the blockade of the CTLA-4-mediated inhibitory pathway is efficacious only in select populations, predominantly for immunogenic tumors or when delivered in combination with modalities that can break immunologic tolerance to tumor antigens. METHODS: We studied the effect of CD25+ cell depletion and CTLA-4 blockade on the growth of Transgenic Mouse Adenocarcinoma of Prostate (TRAMP)-PSA tumor cells in DR2bxPSA F1 mice. In these mice, immunological tolerance to PSA was established in a context of the HLA-DRB1*1501(DR2b) allele. RESULTS: In our model, single administration of anti-CD25 antibody prior to tumor inoculation significantly increased IFN-γ production in response to the CD8 T cell epitope PSA65-73 , and delayed TRAMP-PSA tumor growth compared to mice treated with isotype control antibodies. In contrast, the anti-tumor effect of the anti-CTLA-4 antibody as a monotherapy was marginal. The combinatory treatment with anti-CD25/anti-CTLA-4 antibodies significantly enhanced anti-tumor immunity and caused more profound delay in tumor growth compared to each treatment alone. The proportion of tumor-free animals was higher in the group that received combination treatment (21%) compared to other groups (2-7%). The enhanced anti-tumor immunity in response to the CD25 depletion or CTLA-4 blockade was only seen in the immunogenic TRAMP-PSA tumor model, whereas the effect was completely absent in mice bearing poorly immunogenic TRAMP-C1 tumors. DISCUSSION: Our data suggest that breaking immunological tolerance to "self" antigens is essential for the therapeutic effect of CTLA-4 blockade. Such combinatory treatment may be a promising approach for prostate cancer immunotherapy.

Serum Antibody Repertoire Profiling Using In Silico Antigen Screen.

Serum antibodies are valuable source of information on the health state of an organism. The profiles of serum antibody reactivity can be generated by using a high throughput sequencing of peptide-coding DNA from combinatorial random peptide phage display libraries selected for binding to serum antibodies. Here we demonstrate that the targets of immune response, which are recognized by serum antibodies directed against sequential epitopes, can be identified using the serum antibody repertoire profiles generated by high throughput sequencing. We developed an algorithm to filter the results of the protein database BLAST search for selected peptides to distinguish real antigens recognized by serum antibodies from irrelevant proteins retrieved randomly. When we used this algorithm to analyze serum antibodies from mice immunized with human protein, we were able to identify the protein used for immunizations among the top candidate antigens. When we analyzed human serum sample from the metastatic melanoma patient, the recombinant protein, corresponding to the top candidate from the list generated using the algorithm, was recognized by antibodies from metastatic melanoma serum on the western blot, thus confirming that the method can identify autoantigens recognized by serum antibodies. We demonstrated also that our unbiased method of looking at the repertoire of serum antibodies reveals quantitative information on the epitope composition of the targets of immune response. A method for deciphering information contained in the serum antibody repertoire profiles may help to identify autoantibodies that can be used for diagnosing and monitoring autoimmune diseases or malignancies.

A cytomegalovirus-based vaccine expressing a single tumor-specific CD8+ T-cell epitope delays tumor growth in a murine model of prostate cancer.

Cytomegalovirus (CMV) is a highly immunogenic virus that results in a persistent, life-long infection in the host typically with no ill effects. Certain unique features of CMV, including its capacity to actively replicate in the presence of strong host CMV-specific immunity, may give CMV an advantage compared with other virus-based vaccine delivery platforms. In the present study, we tested the utility of mouse CMV (mCMV)-based vaccines expressing human prostate-specific antigen (PSA) for prostate cancer immunotherapy in double-transgenic mice expressing PSA and HLA-DRB1*1501 (DR2bxPSA F1 mice). We assessed the capacity of 2 mCMV-based vectors to induce PSA-specific CD8 T-cell responses and affect the growth of PSA-expressing Transgenic Adenocarcinoma of the Mouse Prostate tumors (TRAMP-PSA). In the absence of tumor challenge, immunization with mCMV vectors expressing either a H2-D(b)-restricted epitope PSA(65-73) (mCMV/PSA(65-73)) or the full-length gene for PSA (mCMV/PSA(FL)) induced comparable levels of CD8 T-cell responses that increased (inflated) with time. Upon challenge with TRAMP-PSA tumor cells, animals immunized with mCMV/PSA(65-73) had delay of tumor growth and increased PSA-specific CD8 T-cell responses, whereas animals immunized with mCMV/PSA(FL) showed progressive tumor growth and no increase in number of splenic PSA(65-73)-specific T cells. The data show that a prototype CMV-based prostate cancer vaccine can induce an effective antitumor immune response in a "humanized" double-transgenic mouse model. The observation that mCMV/PSA(FL) is not effective against TRAMP-PSA is consistent with our previous findings that HLA-DRB1*1501-restricted immune responses to PSA are associated with suppression of effective CD8 T-cell responses to TRAMP-PSA tumors.

CD4 T-Cell-mediated immune response to prostatic proteins in HLA-DRB1*1503 transgenic mice and identification of a novel HLA-DRB1*1503-restricted T-cell epitope from human prostatic acid phosphatase.

BACKGROUND: Transgenic mice engineered to express human leukocyte antigen (HLA) alleles are widely used for identification of immunogenic and naturally processed epitopes. Using HLA-DRB1*1501 (DR2b) transgenic mice, we have previously identified epitopes from two prostatic antigens, prostate-specific antigen (PSA) and prostatic acid phosphatase (PAP). These antigens are implicated in the development of autoimmunity in the prostate and also are considered promising targets for prostate cancer immunotherapy. HLA-DRB1*1501 is the most common DR15 allele in Caucasians, while HLA-DRB1*1503 is the most common in African Americans. Hence characterization of peptide immunogenicity for these alleles is important for the development of prostate cancer immunotherapy in white and black patients. METHODS: HLA-DRB1*1501 or HLA-DRB1*1503 transgenic mice were immunized with human PSA or PAP. Libraries of overlapping 20-mer peptides spanning the entire sequences of these proteins were screened by IFN-γ ELISPOT assay. RESULTS: PSA and PAP peptides that were previously identified in HLA-DRB1*1501 tg mice were immunogenic in HLA-DR1503 tg mice and induced CD4 T-cell response against whole processed PSA or PAP respectively. However, the hierarchy of the immunodominance among the peptides differed significantly between strains. Using HLA-DRB1*1503 tg mice, a novel immunogenic and naturally processed 20-mer peptide, PAP (233-252) has been identified that showed no reactivity in HLA-DRB1*1501 tg mice. CONCLUSIONS: Our data demonstrate a disparity in CD4 T-cell immune reactivity to PSA and PAP between HLA-DRB1*1501 and -DRB1*1503 alleles in HLA transgenic mouse models. It is possible that such immunological differences could contribute to racial disparity in prostate cancer outcome.

T-cell recognition of prostatic peptides in men with chronic prostatitis/chronic pelvic pain syndrome.

PURPOSE: A potential etiology of chronic prostatitis/chronic pelvic pain syndrome is autoimmunity. We determined whether T cells from men with chronic prostatitis/chronic pelvic pain syndrome would recognize peptides derived from the normal self-prostatic proteins prostate specific antigen and prostatic acid phosphatase. MATERIALS AND METHODS: CD4 T cells purified from peripheral blood of 31 patients with chronic prostatitis/chronic pelvic pain syndrome and from the buffy coat preparation of 27 normal male blood donors were stimulated in vitro with a panel of immunogenic peptides from prostate specific antigen and prostatic acid phosphatase, and assayed for reactivity with the peptides by interferon-gamma enzyme-linked immunosorbent spot assay. Intermediate resolution HLA typing was done by polymerase chain reaction. Peptides were also tested by binding assay against different class II alleles. RESULTS: Peptide PAP(173-192) was recognized more frequently by CD4 T cells from patients with chronic prostatitis/chronic pelvic pain syndrome than from healthy donors. The recognition of prostate specific antigen peptides was not statistically different when comparing cases to normal male blood donors individually. Peptide reactivity was more common in patients than in normal male blood donors for any prostate specific antigen peptide or any tested peptide. All peptides showed high promiscuity on binding assays. There was no association of cases with any specific HLA class II phenotype at intermediate resolution. CONCLUSIONS: CD4 T cells from patients with chronic prostatitis/chronic pelvic pain syndrome have a higher rate of recognizing the self-prostatic proteins prostatic acid phosphatase and prostate specific antigen compared to those from normal male blood donors. Data provide further evidence to support the role of autoimmunity in some men with chronic prostatitis/chronic pelvic pain syndrome.

Vaccination with agonist peptide PSA: 154-163 (155L) derived from prostate specific antigen induced CD8 T-cell response to the native peptide PSA: 154-163 but failed to induce the reactivity against tumor targets expressing PSA: a phase 2 study in patients with recurrent prostate cancer.

We conducted a clinical trial of peptide prostate specific antigen (PSA): 154-163 (155L) vaccination in human leukocyte antigen (HLA)-A2 patients with detectable and rising serum PSA after radical prostatectomy for prostate cancer (Clinicaltrials.gov identifier NCT00109811). The trial was a single dose-level, phase 2 pilot trial of 1 mg of PSA: 154-163 (155L) emulsified with adjuvant (Montanide ISA-51). The primary endpoint was the determination of immunogenicity of the vaccine; secondary outcomes were determination of toxicity and effect on serum PSA. The vaccine was given subcutaneously 7 times on weeks 0, 2, 4, 6, 10, 14, and 18. Peptide-specific CD8 T-cell responses in the peripheral blood mononuclear cells (PBMC) of patients were measured by interferon (IFN)-gamma enzyme-linked immunosorbent spot assay. CD8 T-cell cultures were also established by in vitro stimulation with the peptide presented by autologous dendritic cells. Five patients were enrolled and completed all vaccinations. No IFN-gamma response to PSA: 154-163 (155L) was detected in unfractioned PBMC in any patient either before or after vaccination. Three of 5 patients demonstrated strong IFN-gamma responses to PSA: 154-163 (155L) and native PSA: 154-163 peptides in CD8 T-cell cultures derived from postvaccination PBMC. However, peptide-specific T cells failed to recognize HLA-A2 positive targets expressing endogenous PSA. There were no significant changes in serum PSA level in any subject. No serious adverse events were observed. PSA: 154-163 (155L) is not an effective immunogen when given with Montanide ISA-51. The PSA: 154-163 peptide is poorly processed from endogenous PSA and therefore represents a cryptic epitope of PSA in HLA-A2 antigen-presenting cells.

Cutting edge: permissive MHC class II allele changes the pattern of antitumor immune response resulting in failure of tumor rejection.

We studied the growth of transgenic adenocarcinoma of mouse prostate (TRAMP)-C1 tumor cells expressing human prostate-specific Ag (PSA) in HLA-DRB1*1501 (DR2b) transgenic mice. TRAMP-PSA tumors were frequently rejected by HLA-DR2b(-) mice but had increased incidence in HLA-DR2b(+) littermates. The levels of PSA-specific CD8 T cell responses were significantly higher in the HLA-DR2b(-) mice that rejected TRAMP-PSA tumors compared with HLA-DR2b(+) tumor-bearing littermates. In contrast, Ab responses to PSA were strong in HLA-DR2b(+) mice bearing TRAMP-PSA tumors and were virtually undetectable in HLA-DR2b(-) littermates. The analysis of CD4 T cell responses to PSA revealed the presence of several CD4 T cell epitopes in HLA-DR2b(+) mice but failed to identify strong I-A(b)-restricted epitopes in HLA-DR2b(-) mice. Our data demonstrate that the expression of a permissive HLA class II allele can change the pattern of the immune response to a tumor Ag, resulting in the failure of tumor rejection.

Identification of HLA-DRB1*1501-restricted T-cell epitopes from human prostatic acid phosphatase.

BACKGROUND: The crucial role of CD4 T-cells in anti-tumor immune response is widely recognized, yet the identification of HLA class II-restricted epitopes derived from tumor antigens has lagged behind compared to class I epitopes. This is particularly true for prostate cancer. Based on the hypothesis that successful cancer immunotherapy will likely resemble autoimmunity, we searched for the CD4 T-cell epitopes derived from prostatic proteins that are restricted by human leukocyte antigen (HLA)-DRB1*1501, an allele associated with granulomatous prostatitis (GP), a disease that may have an autoimmune etiology. One of the antigens implicated in the development of autoimmunity in the prostate is prostatic acid phosphatase (PAP), which is also considered a promising target for prostate cancer immunotherapy. METHODS: We immunized transgenic (tg) mice engineered to express HLA-DRB1*1501 with human PAP. A library of overlapping 20-mer peptides spanning the entire human PAP sequence was screened in vitro for T-cell recognition by proliferative and interferon (IFN)-gamma enzyme-linked immunosorbent spot (ELISPOT) assays. RESULTS: We identified two 20-mer peptides, PAP (133-152), and PAP (173-192), that were immunogenic and naturally processed from whole PAP in HLA-DRB1*1501 tg mice. These peptides were also capable of stimulating CD4 T lymphocytes from HLA-DRB1*1501-positive patients with GP and normal donors. CONCLUSIONS: These peptides can be used for the design of a new generation of peptide-based vaccines against prostate cancer. The study can also be helpful in understanding the role of autoimmunity in the development of some forms of chronic prostatitis.