Magnus Hellström

CD4+CD25high T Cells Are Enriched in the Tumor and Peripheral Blood of Prostate Cancer Patients

In this study, we investigated whether CD4+CD25high regulatory T cells (Treg) are increased in the tumor tissue and peripheral blood of early-stage prostate cancer patients undergoing prostatectomy. We show that the prevalence of CD4+CD25high T cells inside the prostate was significantly higher in the tumor compared with benign tissue from the same prostate. Furthermore, the frequency of CD4+CD25high T cells in peripheral blood was significantly higher in prostate cancer patients compared with normal donors. A proportion of the CD4+CD25high T cells was also shown to be glucocorticoid-induced TNF receptor, ICOS, and FOXP3 positive. Moreover, CD4+CD25+ T cells from blood and supernatants from cultured prostate tumor tissue samples exhibited immunosuppressive function in vitro. Furthermore, supernatants from cultured prostate tissue samples and prostate cancer ascites fluid induced migration of CD4+CD25+ T cells and were shown to contain the regulatory T cell chemokine CCL22 by ELISA. Our findings indicate that Tregs are an important cellular component of early-stage prostate tumors, and thus new therapeutic strategies aimed at inhibition or depletion of Tregs may improve prostate cancer immunotherapy.

A phase I trial of DNA vaccination with a plasmid expressing prostate-specific antigen in patients with hormone-refractory prostate cancer.

Prostate-specific antigen (PSA) is a serine protease secreted at low levels by normal luminal epithelial cells of the prostate and in significantly higher levels by prostate cancer cells. Therefore, PSA is a potential target for various immunotherapeutical approaches against prostate cancer. DNA vaccination has been investigated as immunotherapy for infectious diseases in patients and for specific treatment of cancer in certain animal models. In animal studies, we have demonstrated that vaccination with plasmid vector pVAX/PSA results in PSA-specific cellular response and protection against tumour challenge. The purpose of the trial was to evaluate the safety, feasibility and biological efficacy of pVAX/PSA vaccine in the clinic. A phase I trial of pVAX/PSA, together with cytokine granulocyte/macrophage-colony stimulating factor (GM-CSF) (Molgramostim) and IL-2 (Aldesleukin) as vaccine adjuvants, was carried out in patients with hormone-refractory prostate cancer. To evaluate the biologically active dose, the vaccine was administered during five cycles in doses of 100, 300 and 900 μg, with three patients in each cohort. Eight patients were evaluable. A PSA-specific cellular immune response, measured by IFN-γ production against recombinant PSA protein, and a rise in anti-PSA IgG were detected in two of three patients after vaccination in the highest dose cohort. A decrease in the slope of PSA was observed in the two patients exhibiting IFN-γ production to PSA. No adverse effects (WHO grade >2) were observed in any dose cohort. We demonstrate that DNA vaccination with a PSA-coding plasmid vector, given with GM-CSF and IL-2 to patients with prostate cancer, is safe and in doses of 900 μg the vaccine can induce cellular and humoral immune responses against PSA protein.

Clinical characteristics and primary treatment of prostate cancer in Sweden between 1996 and 2005

Objective. The incidence of prostate cancer is rising rapidly in Sweden and there is a need to better understand the pattern of diagnosis, tumor characteristics and treatment. Material and methods. Between 1996 and 2005, all new cases of adenocarcinoma of the prostate gland were intended to be registered in the National Prostate Cancer Register (NPCR). This register contains information on diagnosing unit, date of diagnosis, cause of diagnosis, tumor grade, tumor stage according to the TNM classification in force, serum prostate-specific antigen (PSA) levels at diagnosis and primary treatment given within the first 6 months after diagnosis. Results. In total, 72 028 patients were registered, comprising >97% of all pertinent incident cases of prostate cancer in the Swedish Cancer Register (SCR). During the study period there was a considerable decrease in median age at the time of diagnosis, a stage migration towards smaller tumors, a decrease in median serum PSA values at diagnosis, a decrease in the age-standardized incidence rate of men diagnosed with distant metastases or with a PSA level of >100 ng/ml at diagnosis and an increase in the proportion of tumors with Gleason score ≤6. Relatively large geographical differences in the median age at diagnosis and the age-standardized incidence of cases with category T1c tumors were observed. Treatment with curative intent increased dramatically and treatment patterns varied according to geographical region. In men with localized tumors and a PSA level of <20 ng/ml at diagnosis, expectant treatment was more commonly used in those aged ≥75 years than in those aged <75 years. Also, the pattern of endocrine treatment varied in different parts of Sweden. Conclusions. All changes in the register seen over time are consistent with increased diagnostic activity, especially PSA testing, resulting in an increased number of cases with early disease, predominantly tumors in category T1c. The patterns of diagnosis and treatment of prostate cancer vary considerably in different parts of Sweden. The NPCR continues to be an important source for research, epidemiological surveillance of the incidence, diagnosis and treatment of prostate cancer

Clinical outcome in patients with prostate cancer treated with external beam radiotherapy and high dose-rate iridium 192 brachytherapy boost: A 6-year follow-up

To report the long-term results for treatment of localized carcinoma of the prostate using high dose rate (HDR) brachytherapy, conformal external beam radiotherapy (3D EBRT) and neo-adjuvant hormonal therapy (TAB). From 1998 through 1999, 154 patients with localized prostate cancer were entered in the trial. Biologically no evidence of disease (bNED) was defined at PSA levels < 2 µg/l. In order to compare the results of this treatment with other treatment modalities, the patients pre-treatment data were used to calculate the estimated 5-year PSA relapse free survival using Kattans nomograms for radical prostatectomy (RP) and 3D EBRT. After 6 years of follow-up, 129 patients remain alive. The actual 5-year relapse-free survival is 84%. None of the patients demonstrated clinical signs of local recurrence. The median PSA at follow-up among the relapse-free patients was 0.05 µg/l. Among the 80 patients who presented with clinical stage T3 tumours, 55 (68%) were relapse-free. The expected 5-year relapse-free survival using nomograms for RP and 3D EBRT was 54% and 70%, respectively. Late rectal toxicity RTOG grade 3 occurred in 1% of the patients. Late urinary tract toxicity RTOG grade 3 developed in 4% of the patients. Combined treatment, utilizing HDR, 3D EBRT and TAB, produces good clinical results. Rectal toxicity is acceptable. Urinary tract toxicity, most likely can be explained by the fact that during the first years of this treatment, no effort was made to localize the urethra, which was assumed to be in the middle of the prostate.

Non-systematic screening for Prostate Cancer in Sweden: Survey from the National Prostate Cancer Registry

Objective: The large increase in the incidence of prostate cancer is largely due to testing of serum levels of prostate‐specific antigen (PSA). Little is known about how PSA testing is used in clinical practice outside of screening programmes. Essentially, PSA can be used in the health check‐ups of men without symptoms as a form of non‐systematic screening or in the work‐up of symptomatic patients. The aim of this study was to investigate the cause of initiating a work‐up leading to a diagnosis of prostate cancer, with emphasis on T1c tumours. Material and Methods: Data on the cause of initiation of work‐up leading to a diagnosis of prostate cancer were retrieved from the National Prostate Cancer Registry for 6361 incident cases in tumour category T1c and local stages T2, T3 and T4 registered in Sweden in 2000. Results: For 1496 cases in tumour category T1c (non‐palpable tumours detected during work‐up of elevated PSA), the cause of PSA testing was health check‐ups in 32% of cases, work‐up of symptoms suspected to emanate from the prostate in 51% and other causes/not reported in 17%. For all stages combined, the cause of initiation of the diagnostic work‐up was health check‐ups in 18% of cases, symptoms in 68% and other causes/not reported in 14%. Conclusion: Non‐systematic screening using PSA testing has been introduced in Sweden. However, prostate cancer is still most commonly diagnosed during the work‐up of symptomatic patients.

Geographical variation in incidence of prostate cancer in Sweden.

Objective. To investigate the geographical variation in prostate cancer incidence in Sweden, in particular the incidences of screening-detected tumours and curative treatment of prostate cancer. Material and methods. Data were retrieved from the National Prostate Cancer Register of Sweden for all cases of prostate cancer diagnosed in the year 2000–01. There were a total of 14 376 cases of prostate cancer and the mean total annual age-adjusted incidence was 197/100 000 men. There were 3318 cases in tumour category T1c, i.e. non-palpable tumours diagnosed during work-up for an elevated serum level of prostate-specific antigen, 1006 of which (30%) were asymptomatic and detected at a health check-up. Results. The difference between the counties with the lowest and highest age-adjusted incidences per 100 000 men of total prostate cancer was almost twofold (128 vs 217). The corresponding variation in incidence of category T1c tumours was more than fourfold (13 vs 60); the difference in incidence of T1c tumours detected in asymptomatic men was up to 10-fold (2 vs 20); and there was more than a fourfold variation in incidence of curative treatment between counties (13 vs 67). Measured incidences were mostly highest in urban regions and in counties with university hospitals. Conclusion. There are large geographical variations in prostate cancer incidence and in the frequency of curative treatment for prostate cancer in Sweden and there appear to be large geographical variations in the uptake of prostate cancer screening.

[11C]Acetate positron emission tomography-computed tomography imaging of prostate cancer lymph-node metastases correlated with histopathological findings after extended lymphadenectomy.

Abstract Objective.The aim of this study was to determine the efficacy of combined [11C]acetate positron emission tomography and computed tomography ([11C]acetate-PET/CT) in regional lymph-node staging in patients with prostate cancer (PCa). Material and methods. [11C]Acetate-PET/CT was performed in 19 PCa patients who subsequently underwent extended pelvic lymph-node dissection (ePLND). The [11C]acetate-PET/CT results were compared with the surgical and histopathological findings from 13 defined lymph-node regions. Results.[11C]Acetate-PET/CT was true-positive for lymph-node metastases in nine patients, false-positive in three, false-negative in one patient and true-negative in six. The patient-by-patient-based sensitivity was 90% and the specificity 67%, the positive predictive value (PPV) was 75% and the negative predictive value (NPV) 86%. From a total of 114 nodal regions (mean 5.9 regions per patient), 484 lymph nodes (mean 25.5 nodes per patient) were removed and evaluated histopathologically. Forty-six lymph nodes from 24 out of 114 (21%) nodal regions were positive for PCa metastasis. The nodal-region-based sensitivity of [11C]acetate-PET/CT was 62%, specificity was 89%, PPV 62% and NPV 89%. Conclusion. [11C]Acetate-PET/CT detects PCa lymph-node metastases with high patient-by-patient-based sensitivity but low specificity, and low nodal-region-based sensitivity but high specificity. Its limited ability to detect microscopic lymph-node involvement makes ePLND essential in all patients diagnosed with positive nodes on [11C]acetate-PET/CT.

Atypical stromal hyperplasia of the prostate

This paper reports a case of atypical stromal hyperplasia (ASH) of the prostate, i.e. a proliferation of stromal cells with scattered atypical nuclei, growing between benign prostatic glands. This is a rare lesion, but at least 36 cases have been reported. Although most ASHs arise in the transition zone in conjunction with benign prostatic hyperplasia, the current lesion was found in the peripheral zone of a 58-year-old man who underwent radical prostatectomy because of prostatic adenocarcinoma. The clinical impact of ASH is discussed and the literature reviewed.

Proteomics in clinical prostate research.

The incidence of early prostate cancer (PCa) has increased rapidly in recent years. The majority of newly diagnosed PCa are in early tumor phase. Presently, we do not have adequate biomarkers to assess tumor aggressiveness in individual cases. Consequently, too many patients are given curatively intended treatment. An exploration of the human proteome may provide clinically useful markers. 2‐DE has been successfully used for analysis of the protein phenotype using clinical samples. Proteins are separated according to size and charge, gels are compared by image analysis, protein spots of interest are excised, and proteins identified by MS. This method is exploratory and allows protein identification. However, low‐abundance proteins are difficult to detect and 2‐DE is currently too labor‐intensive for routine use. In recent years, nongel based techniques, such as LC‐MS, SELDI‐MS, and protein arrays have emerged. They require smaller sample sizes and can be more automated than 2‐DE. In this review, we describe studies of the protein expression of benign prostatic tissue and PCa, which is likely to serve as the first step in prognostic biomarker discovery. The prostate proteome is still far from a complete mapping which would enhance our understanding of PCa biology.

Prevalence of prostate cancer at different levels of serum prostate-specific antigen (PSA) and different free : total PSA ratios in a consecutive series of men referred for prostate biopsies

Objective. In this retrospective study we report on the detection rate of prostate cancer (PCa) at different levels of prostate-specific antigen in serum (s-PSA) and at different PSA ratios (free:total PSA) during a 2-year period in patients without previously known PCa. Material and methods. During the years 2001 and 2002, 361 consecutive patients were examined with ultrasound-guided core needle biopsies at our department. The patients were biopsied due to an increased s-PSA level, a low PSA ratio or findings at digital rectal examination (DRE). Patients with previously known cancer (T1a/b or cancer already detected with fine-needle aspiration cytology) were excluded. We used the BioPince® biopsy needle, which has a stroke length of 32 mm. In 91% of the patients, eight biopsies were taken from the apex, mid-medial, mid-lateral and base positions bilaterally. Results. Of the 361 patients, 188 (52%) had PCa. Most cancers were T1c or T2 tumors (51% and 34%, respectively). Among patients with an s-PSA level of < 4 ng/ml, 8/35 (23%) had PCa. Five of 13 patients with a normal DRE (T1c) and an s-PSA level of < 4 ng/ml had PCa. In total, in the PSA ratio intervals 0.05–0.1 and 0.11–0.17, cancer was found in 71% and 51% of cases, respectively. In contrast, only 35% of patients had positive biopsies when the PSA ratio was normal (p<0.01). Conclusions. The overall cancer detection rate was high and a large proportion of patients with an s-PSA level of < 4 ng/ml had PCa. The risk of having PCa increased considerably with a low PSA ratio.