Why are pretreatment prostate‐specific antigen levels and biochemical recurrence poor predictors of prostate cancer survival?

BACKGROUND:

The value of pretreatment (initial) prostate‐specific antigen (iPSA) and biochemical recurrence (BR) as prognostic factors for survival remains unclear. The authors sought to determine why using randomized trial data with 7‐year minimum follow‐up.

METHODS:

In the Trans‐Tasman Radiation Oncology Group 96.01 trial, 802 men with T2b, T2c, T3, or T4 N0 prostate cancer (PC) were randomized to radiotherapy alone or with 3 or 6 months neoadjuvant androgen deprivation between 1996 and 2000. Cox modeling was used to identify outcome predictors at follow‐up landmark points.

RESULTS:

Higher iPSA was found to be a potent predictor of BR–free survival (P < .01) but was not prognostic for prostate cancer–specific survival (PCSS) from randomization. Patients experiencing BR had unfavorable initial prognostic factors compared with patients who did not. After BR, these factors were not prognostic for PC death in models adjusted for time to BR (TTBR). In these models, TTBR predicted PCSS more satisfactorily than the occurrence of BR itself. Survival probability 5 years after BR exceeded 90% for men with TTBR ≥4 years; however, it dropped to 44% ± 6% for men with TTBR <1 year. After BR, rapid PSA doubling time (DT), low iPSA, and short TTBR were identified as the most important predictors of inferior PCSS.

CONCLUSIONS:

When BR occurs, prognostic factors for survival change. Low iPSA, short TTBR, and rapid PSA DT take over at this point, providing reasons why iPSA and occurrence of BR alone predict PCSS unsatisfactorily. Cancer 2009. © 2009 American Cancer Society.     

Strontium‐89 treatment for prostate cancer bone metastases: Does a prostate‐specific antigen response predict for improved survival?

A review of 50 patients treated with strontium‐89 for prostate cancer bone metastases from January 1993–1997 at the Wellington Cancer Centre was undertaken to determine if there was any correlation between changes in prostate‐specific antigen (PSA) following treatment and subsequent survival. Thirty cases were evaluable for PSA response. Of these, 14 had a fall in PSA following strontium‐89 treatment, and their mean survival was 641 days. The remaining 16 patients did not demonstrate a post‐treatment fall in PSA and their mean survival was 275 days. A difference between these two groups in the time to development of new bone symptoms following treatment was also observed. No significant correlation between pretreatment PSA and PSA response was observed. In conclusion, a PSA response following strontium‐89 treatment appears to predict for improved survival in patients with bone metastases from carcinoma of the prostate. Further prospective studies are indicated.     

Prostate specific antigen — a new constituent of breast cyst fluid

Summary We demonstrate for the first time that prostate specific antigen (PSA) is a component of breast cyst fluid. At the cutoff level of 0.01 or 0.03 µg/L of PSA, 64% or 43% of cyst fluids are positive for PSA, respectively. PSA in cyst fluid, as characterized by high performance liquid chromatography, exists in almost equal concentrations as free PSA, with a molecular weight of 33 KDa, and as PSA bound to ₁-antichymotrypsin, with a molecular weight of 100 KDa. PSA presence was also characterized in cyst fluid by Western blot analysis. These data suggest that PSA is a frequent component of breast cyst fluid. More studies are needed to establish the role of this serine protease in normal breast, gross breast cystic disease, and breast cancer.     

Are importance–satisfaction discrepancies with regard to ratings of specific health‐related quality‐of‐life aspects valid indicators of disease‐ and treatment‐related distress among patients with endocrine gastrointestinal tumours?

The aims of this study were to investigate: (1) whether ratings of importance of, satisfaction with, and symptom/function of specific health-related quality-of-life (HRQoL) aspects are related, and (2) whether an importance–satisfaction discrepancy with regard to ratings of a specific HRQoL aspect is a valid indicator of distress. Eighty-three patients with endocrine gastrointestinal tumours completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and answered questions about importance of, satisfaction with, and symptom/function of 12 HRQoL aspects. The patients reported a relatively high HRQoL in terms of physical, emotional and social function. Most of the HRQoL aspects were considered as important for a good quality of life. High satisfaction was related to fewer symptoms and a better function. Patients who assigned a higher importance than satisfaction rating to an aspect reported a lower quality of life for the same aspect. The findings suggest that importance–satisfaction discrepancies are valid indicators of patient distress and illustrate the importance of asking patients not only about frequency and level of symptoms, but also about importance of and satisfaction with when assessing patient quality of life.     

Prostate specific antigen: a useful screening test?

The role of prostate specific antigen (PSA) as a screening test for prostate cancer is controversial. Proponents of screening emphasize that early detection can lead to discovery of organ-confined disease and the potential for cure. Opponents point to the lack of credible evidence that screening is associated with a decrease in mortality. In addition, population-based screening (with subsequent diagnosis and treatment in many men) can be associated with considerable morbidity and mortality in the context of a disease that is often not fatal. This report examines the limitations of PSA as a screening test and supports an approach using "verbal informed consent" to identify patients who should be tested.     

Immunohistochemical labelling for prostate–specific antigen in breast carcinomas

Immunohistochemical detection of prostate–specific antigen (PSA) is an aid in determining the prostatic origin of metastatic cells. However, small amounts of PSA have also been found in non–prostatic tissues and tumors, for example in some breast carcinomas, by highly sensitive immunofluorometric methods, but also by immunohistochemistry. Our aim was to evaluate the prevalence and prognostic value of histologically confirmed PSA immunoreactivity in breast carcinoma.Sections of formalin–fixed, paraffin–embedded samples from 171 breast carcinomas were immunostained for PSA. The staining results were compared with the mitotic activity, tumor size, histological grade, steroid receptors and follow–up data. For analysis the material was divided into subgroups according to the patients' age (pre- and postmenopausal). PSA was found by immunohistochemistry in 54 (32) breast carcinomas. In survival analysis of the whole patient material PSA positivity did not show prognostic value. Among premenopausal patients concomitant estrogen receptor and PSA–negativity proved to be associated with high risk of breast cancer death (RR 6.2), also after adjustment for tumor size, histological grade, and axillary lymph node status. Among postmenopausal patients PSA positivity was associated with progesterone receptor positivity and high differentiation but not with age, nodal status, or mitotic activity. PSA can be detected by immunohistochemistry in a considerable number of breast carcinomas. PSA immunoreactivity alone does not seem to have any value as general prognosticator of breast carcinoma patients. However, concomitant absence of PSA and estrogen receptors was an indicator of unfavourable prognosis among premenopausal patients.     

Biomarkers of oxidant load and type‐specific clearance of prevalent oncogenic human papillomavirus infection: Markers of immune response?

Human papillomavirus (HPV) infection is the cause of cervical cancer. Increased production of reactive oxygen species (ROS) maybe the common mechanism through which HPV-cofactors (i.e., smoking and inflammation) influence duration of infections. Biomarkers of total oxidant load may serve as cumulative measures of ROS exposure due to these cofactors. Therefore, we conducted a study evaluating the association between biomarkers of oxidant load and duration of HPV infections, early HPV natural history events. Serum samples were obtained from 444 HPV-positive women in the Ludwig-McGill Cohort Study. Anti-5-hydroxymethyl-2'-deoxyuridine autoantibody (anti-HMdU aAb) and malondialdehyde (MDA) were measured at baseline. Cox-proportional hazard models were used to estimate the probability of clearing any HPV, oncogenic HPV, non-oncogenic HPV and HPV-16 infections. Women with elevated MDA were significantly more likely to clear prevalent oncogenic HPV infections compared to those with lower MDA levels (Adjusted Hazard Ratio (AHR) = 2.7; 95%CI = 1.4-5.1). There did not appear to be an association between elevated MDA and clearance of incident oncogenic HPV infections. Similarly, women with elevated anti-HMdU aAb levels had higher rates of prevalent oncogenic HPV infection clearance (Quartile 3:AHR = 2.2; 95%CI = 1.2-4.4; Quartile 4:AHR = 2.4; 95%CI = 1.2-4.9). Higher levels of oxidant load biomarkers were associated with increased clearance of prevalent HPV infections. However, oxidant load biomarkers measured before incident infections were not associated, suggesting that the elevation of MDA and anti-HMdU aAb may reflect an ongoing effective immune response, such as increased innate immunity. More research focused on the immune responses to HPV and elevated markers of oxidant load is needed.     

Cytoplasmic melanoma‐associated antigen (CYT‐MAA) serum level in patients with melanoma: A potential marker of response to immunotherapy?

Simple, noninvasive methods are needed to follow effectiveness of new treatments in patients with melanoma. In our study, we examined cytoplasmic melanoma-associated antigen (CYT-MAA) serum level in melanoma patients during immunotherapy. Sera of 117 patients were assayed for CYT-MAA by double-sandwich ELISA before and during treatment with a polyvalent, shed antigen, melanoma vaccine. Vaccine-treated patients included 30 with American Joint Committee on Cancer (AJCC) stage IIb or IIIa, 30 with stage IIc, IIIb or IIIc, 30 with resected stage IV and 27 with measurable stage IV disease. Prior to vaccine therapy, 63% of patients had elevated serum CYT-MAA with high levels of antigen in all disease stages. After initiation of therapy, the level declined in more than 90% of the positive patients and fell below the positive cut-off in 56% of these patients within 5 months. By contrast, there was no decline in CYT-MAA serum level in 11 patients who served as untreated controls with melanoma. Multivariate analysis of the treated patients using accelerated failure time Weibull models adjusted for stage and age showed that patients whose CYT-MAA serum level remained elevated during treatment were approximately 3 times more likely to recur or progress than patients who were consistently below the positive cut-off (hazard ratio = 3.42, 95% CI [1.38, 8.47], p = 0.0079). Measurement of CYT-MAA serum level appears to show potential as an early marker of prognosis in patients with stages IIb to IV melanoma. Measurement of CYT-MAA serum level during therapy could provide an intermediate marker of response in these patients.     

Individual variations of total and percent free serum prostatic specific antigen: could they change the indication of prostatic biopsy?

The aim of this study was to analyse the individual variations of total and percent free serum prostatic specific antigen (PSA) and to evaluate whether they could change the indication for prostatic biopsy. Prostatic needle biopsy was indicated in 63 patients with serum PSA between 4.0 and 10 ng/ml. A new determination of total and free PSA was done before the biopsy procedure. The time between the determinations ranged from 29 to 59 days. The total and free serum PSA determinations were performed by a double monoclonal antibody radioimmunoassay Tandem and Tandem free PSA. The median coefficient of variation for serum PSA was 12.9 in cancer free patients and 18.8 when cancer was detected, it was 32.6 and 42.2 respectively for percent free serum PSA. A 22.8% rate of discrepancy between the determinations was found when prostatic biopsy was indicated only by percent free PSA lower than 25. Sensitivity ranged from 93.3% to 100, and reduction of unnecessary biopsies between 15.2 and 21.8%. We conclude that individual variations in total and percent free serum PSA could have clinical implications because of the possibility that it changes the indication for a prostatic biopsy.     

Prostate cancer diagnosis: should patients with prostate specific antigen >10 ng/mL have stratified prostate biopsy protocols?

Background: Trans-rectal ultrasound (TRUS) guided systematic prostate biopsy is a standard tool in prostate cancer (CaP) diagnosis. Extended biopsy techniques using 10-12 cores are the norm. Controversy exists on extended TRUS biopsy in men with PSA >10 ng/mL. We evaluated cancer detection rates on an individual core basis, to stratify prostate biopsy protocols based on PSA levels. Patients and methods: Over a five-year period, 1036 patients underwent TRUS guided prostate biopsy for raised serum PSA (>2.5 ng/mL). 436 patients had PSA >10 ng/mL. Patients with PSA <50 ng/mL underwent a 12-core TRUS guided prostate biopsy including six peripheral biopsies. The six peripheral biopsies were directed laterally towards the base, mid-zone and apices. Remainder were standard para-sagittal sextant biopsies. Patients were stratified into three groups (PSA 10-20 ng/mL, 20-50 ng/mL and >50 ng/mL). Results: Mean age of 436 patients with PSA >10 ng/mL was 70.3years. 270 (62%) men had cancer. Cancer detection rates for different PSA levels were 46% (10-20 ng/mL), 76% (20-50 ng/mL) and 93% (>50 ng/mL). Higher PSA levels and advanced clinical stage were associated with increased cancer detection rates. All patients with clinical T3 and T4 disease had biopsy diagnosed CaP. Conclusion: TRUS guided prostate biopsy in patients with PSA >10 ng/mL did not require 12 cores to diagnose CaP. CaP diagnosis required 8 cores in men with PSA 10-20 ng/mL. These cores were right and left peripheral basal and apical, and right and left para-sagittal basal and apical biopsy. Only 6 cores were necessary to diagnose CaP in men with PSA >20 ng/mL which were right and left peripheral basal and apical, and para-sagittal apical biopsies. We suggest limited TRUS prostate biopsy protocols for men with PSA >10 ng/mL.     

Anti‐tumour/metastasis effects of the potassium‐sparing diuretic amiloride: An orally active anti‐cancer drug waiting for its call‐of‐duty?

Amiloride.HCl is clinically used as an oral potassium-sparing diuretic, but multiple studies in biochemical, cellular and animal models have shown that the drug also possesses anti-tumour and anti-metastasis activities. The additional effects appear to arise through inhibition of two discrete targets: (i) the sodium-hydrogen exchanger 1 (NHE1), a membrane protein responsible for the characteristically low extracellular pH of tumours and (ii) the urokinase-type plasminogen activator (uPA), a serine protease mediator of cell migration, invasion and metastasis and well-known marker of poor prognosis in cancer. This mini-review summarises for the first time the reported anti-tumour/metastasis effects of amiloride in experimental models, discusses the putative molecular mechanisms responsible for these effects and concludes by commenting on the pros and cons of trialling amiloride or one of its structural analogues as potential new anti-tumour/metastasis drugs.     

Does ampicillin‐sulbactam cause false positivity of (1,3)‐beta‐D‐glucan assay? A prospective evaluation of 15 patients without invasive fungal infections*

The purpose of this study was to investigate the interaction between intravenous ampicillin‐sulbactam treatment and (1,3)‐beta‐D‐glucan (BDG) assay. Fifteen patients with a median age of 60 (16–81) without known risk factors for invasive fungal infections who received a daily dose of 3 × 2 g ampicillin‐sulbactam monotherapy from different batches were included in the study. Thirteen patients had soft tissue infections. The 5 of 13 patients who went under surgery had surgical dressings. Serum samples were obtained both before and after antibiotic infusion on the first, third, seventh and tenth days of an ampicillin‐sulbactam treatment course. BDG was assayed using the Fungitell kit (Associates of Cape Cod, East Falmouth, MA, USA) according to manufacturers’ specifications. All serum samples were also tested for galactomannan (GM) antigenemia by Platelia Aspergillus ELISA (Bio‐Rad Laboratories, Marnes‐la‐Coquette, France). A total of 37 of 117 serum samples were positive for BDG at a threshold of 80 pg ml^?1. Seven of 37 BDG positive serum samples had a GM index ≥0.5. When a cutoff value of ≥0.5 was used for GM positivity, 16 (13.3%) serum samples were positive. For a cutoff value of ≥0.7, eight (6.6%) serum samples were positive. There were no statistically significant differences in the median BDG levels (P = 0.47) or median GM indices (P = 0.28) of the various sampling times. None of the SAM vials tested positive for BDG or GM. After ruling out fungal infections and all known potential causes of false BDG positivity, environmental contamination remained possible cause of BDG reactivity. We did not observe any significant association of ampicillin‐sulbactam administration and positive assays for BDG or GM.     

The lady with raised prostate specific antigen: do we need to worry?

Background: Prostate specific antigen (PSA) is generally considered a biological marker of prostate cancer although raised values may also be observed in benign prostatic diseases. PSA can be secreted in females from skeine’s periurethral gland but at low levels. This case - control study aimed at the evaluation of relation of PSA with different diseases in women. Method: A total of 297 patients were included, 107 with breast cancer, 90 with benign breast disease (BBD) and 100 controls (patients attending our surgery department for non-breast diseases). PSA was measured in the serum of all and a statistical analysis was conducted. Result: An association of raised PSA with breast diseases was observed. Total PSA was more sensitive for benign breast diseases, whereas breast cancer showed a predilection towards increase in free PSA. PSA decreased after surgery. Conclusion: PSA can be used as a diagnostic and prognostic marker of breast cancer in women, therefore helping secondary prevention of breast cancer.     

What is the role of the (1→3)‐β‐d‐glucan assay in the screening of patients undergoing autologous haematopoietic stem‐cell transplantation?

The aim of this study is to determine the clinical contribution of (1→3)‐β‐d ‐glucan (BDG) screening in the case of patients undergoing autologous haematopoietic stem‐cell transplantation (HSCT). The records at our stem‐cell transplantation centre were reviewed to identify the patients who underwent autologous HSCT between April 2009 and December 2010. Patients were classified as having proven invasive aspergillosis (IA), probable IA, or possible IA on the basis of the criteria established by the European Organization for Research and Treatment of Cancer and Mycoses Study Group (independent of the BDG results). During the study period, the patients were screened for BDG twice a week from transplant (day 0) until engraftment. Three patients were diagnosed with probable IA and five were diagnosed with possible IA. A total of 354 serum samples from79 patients who met the study inclusion criteria were used for statistical analysis. At the cut‐off value of 80 pg ml^?1, the sensitivity was 27.2% [95% confidence interval (CI); 7.3–60.6]; specificity, 94.4% (95% CI; 91.3–96.5); positive predictive value, 6.2%; and negative predictive, 93.7%. The clinical contribution of the BDG assay as a screening test was relatively limited in this cohort of patients undergoing autologous HSCT.     

Is self‐efficacy a predictor of short‐term post‐surgical adjustment among Chinese women with breast cancer?

BACKGROUND: High self-efficacy (SE) is regarded as beneficial for cancer patients in facilitating adaptation and therefore desirable. However, this may not always be the case. DESIGN: A longitudinal cohort study of women receiving breast cancer surgery. Path analysis examined impact of high and low baseline SE scores on outcome. Post hoc analysis stratified outcome expectations by SE. METHODS: 405/529 eligible Chinese women aged 28-79 years receiving breast cancer surgery in six regional Hong Kong hospitals were interviewed within 1 week of surgery. After assessing SE, incongruence between expectancy and outcome of surgery (E-OI), and psychological morbidity, 91% of women were followed for 1 month when psychological and social morbidity were assessed (follow-up). RESULTS: After adjustment for demographic and histopathological factors, psychological morbidity was predicted by E-OI. Women with high E-OI had more impairment of sexuality and self-image. Women with high SE had better self-image and relationships with friends, but tended to underestimate the negative consequences of surgery on appearance. This increased E-OI and thereby psychological morbidity. CONCLUSIONS: High post-surgical SE benefits early social adaptation, but also leads to under-estimating the negative impacts of surgery, impairing psychological adjustment. High SE can thereby contribute indirectly and significantly to increased psychological morbidity.     

What is the Price of survival in Hodgkin's lymphoma? Long‐term follow‐up of cured patients

The paper investigates the late complications of cured Hodgkin's lymphoma (HL) patients. Ninety cured HL patients between 1975 and 1994 were examined. The mean ages of patients at the time of diagnosing HL, and the median period of survival after diagnosis were 32 (11-70) years and 18 (10-30) years, respectively. Among the 90 patients, 73 are still alive, there is no information about 9 and 8 patients died, second malignant disease being the cause of death in 4 of them. Relapse was observed in 24 patients, of which 19 recovered after relapse and were included in the study then. Five patients had late relapse. In 38% of patients, cardiovascular changes, while in 32% pulmonary and pleural damages were observed. Disorders of the thyroid gland, overwhelmingly hypothyroidism, were found in 24%. Less frequently, a second malignant tumour (9%), damage to the skin, musculature, bones and genitourinary system (6%) as well as the gastrointestinal system could be detected. Treatment based on modern therapeutic approaches is expected to decrease the incidence of complications. Still the aim is early detection through close patient follow-up, which may improve the quality of life and decrease mortality as a result.     

Is screening for prostate cancer with prostate specific antigen an appropriate public health measure?

Screening and treatment for prostate cancer is controversial. In the absence of randomized trials, several prominent medical organizations in the United States and Europe have formulated policies that range from enthusiastic support to significant skepticism concerning the efficacy of screening and subsequent treatment for prostate cancer. Sharp rises in the incidence of prostate cancer have occurred whenever PSA testing has been introduced on a wide scale. Unfortunately, it is unclear whether declines in prostate cancer mortality can be attributed to PSA testing. Other explanations include the early use of anti-androgen therapy or changes in environmental factors such as diet. Repeated testing for serum PSA has produced significant shifts in the types of cases being identified and has raised the possibility of significant over-diagnosis of this disease. The European screening trial and the PLCO trial in the US will hopefully provide some insights into the value of population-based testing.     

Angiosarcoma of the Breast – specific findings of MRI

We present a case of low-grade angiosarcoma of the breast. A 26-year old woman presented with a lump in the left breast. An elastic hard and ill-defined tumor, 80 x 50 mm in size, was palpated in the upper region of her left breast. Mammography showed a dense lesion with poorly defined border. Ultrasonography showed a hyper-and hypo-echoic lesion with an unclear border, but no definite tumor. Fine needle aspiration cytology showed no evidence of malignancy. Therefore, she was followed with a diagnosis of mastopathy. Six months later, the lump got enlarged. A contrast-enhanced MRI of the breast was performed. It showed a 100 x 60 mm enhancing vascular mass. Most parts of the tumor enhanced remarkably at the early phase, and prolonged enhancement was recognized at the late phase. Core needle biopsy was performed, and a possible angiosarcoma was diagnosed. It is not easy to diagnose the mammary angiosarcoma. MRI may contribute to the accurate diagnosis and play an important role regarding this entity.