Evaluation of cellular immunologic responsiveness in the clinical management of patients with prostatic cancer. II. Effect of oestrogen, cryosurgery and transurethral resection on thymic-dependent lymphocytic blastogenesis.

The effect of oestrogen, cryosurgery and transurethral resection (TUR) of the prostate on the blastogenic response of thymic-dependent peripheral blood lymphocytes (PBL) to the non-specific mitogen, phytohaemagglutinin (PHA) was evaluated as one in vitro criteria of each of these treatment modalities on the cellular immunologic responsiveness of 24 patients with prostatic cancer. A depression 5 days following receipt of oestrogen and 2-7 days following cryosurgery or TUR of the responsiveness of PHA-stimulated PBL was observed. Oestrogen-induced aberrations of responsiveness may not only be of relevance in prostatic cancer patients, but also suggested association between uterine cancer and prolonged administration of diethylstilboesterol and the development of vaginal tumours in offspring found in association with maternal ingestion during pregnancy. Particularly striking was that contrary to the reduced responsiveness of PBL cultured in autologous and homologous serum from patients receiving TUR, patients receiving cryosurgery, while also showing reduction in autologous serum, showed increased responsiveness when cultured in homologous serum. Although transient, depression of lymphocyte responsiveness, particularly if involving tumour-cloned T cells, may provide reduced surveillance to potential tumour cells leading to an alteration of tumour-host homeostasis. The potential of reduced tumour surveillance at least in the case of TUR, appears to be supported by observations that patients expiring from prostatic cancer at our institution had an antecedent TUR. The possibility of identifying those patients possessing aberrations of responsiveness prior to therapy, as well as those prone to develop or undergo further reduction in their responsiveness following the presently evaluated treatment modalities would appear to be of real and relevant concern in the management of the patient with prostatic, as well as other types of malignant neoplasms. The possibility of pre-operative and/or post-operative immunotherapy in such patients may be indicated pending further study.     

Evaluation of cellular immunologic responsiveness in the clinical management of patients with prostatic cancer. I. Thymic-dependent lymphocytic blastogenesis.

Thymic-dependent lymphocytic blastogenesis of peripheral blood lymphocytes of 59 patients with varying stages of prostatic cancer to the non-specific plant mitogen, phytohaemagglutinin (PHA) and the correlation of their responsiveness with the clinical stage of malignancy and level of alpha2-globulin have been evaluated. Patients within each of the four stages of malignancy possessed statistically significant extrinsic (noted in 40 (68%) of 59 patients) and intrinsic (noted in 21 (47%) of 45 patients) aberrations of their lymphocytic responsiveness to PHA compared with the responsiveness of a control population of non-cancer patients. The observed aberrations were, however, not significantly different between each stage nor did they correlate with the stage of disease. Similarly, levels of alpha2-globulin, while significantly elevated within each stage, as compared with the levels in the control population, no significant differences or correlation with the stage of disease was observed. Of interest, perhaps pending further study, were observations of the increased frequency of the number of patients with a significant elevation of alpha2 with a progression of malignancy from localized to invasive and metastatic disease. A similar trend in the incidence of the association of aberrations of lymphocytic reactivity with elevated levels of alpha2 were also noted with a progression of disease. The present confirmatory observations of a recent study in this laboratory of diminished cellular responsiveness in patients with prostatic cancer may be of considerable relevance in directing the therapeutic management of the patient - lest the therapy selected be further debilitating providing reduced surveillance - metastization of tumour cells, and alteration of tumour-host homeostasis.     

Early results of the Finnish Multicentre Study of Prostatic Cancer (Finnprostate)

Four hundred and four prostatic cancer patients diagnosed in the years 1979-1982 in nine Finnish hospitals have been followed up for a mean period of three years. The aim of this study is to evaluate the situation of this malignancy in the Finnish male population and to discuss the diagnostic procedures and treatment modalities. In one fifth of the patients the carcinoma was as incidental finding on microscopical examination of tissue removed by transurethral resection or enucleation for presumed benign prostatic hyperplasia. At the diagnostic moment 69% of the tumours were locally advanced beyond the prostatic capsule and one third of all cases had metastasized. 134 out of 404 (33%) have died and 45% of these of prostatic cancer. Survival was adversely affected by the tumour differentiation grade. In non-metastasized cases the local extent of the tumour had no notable effect on prognosis. Some early comparisons are made between orchidectomy and oestrogen therapy.     

Recent data on the mechanism of action of oestrogens in the treatment of prostatic tumour patients

The authors administered¹³¹I labelled estramustine-phosphate (Estracyt^R) to 15 healthy adult individuals and to 15 prostatic hypertrophic resp. 30 prostatic tumour patients supposing the important role of prostatic cells dependent on the hormonal system in the oestrogen metabolism and the uptake of oestrogenic substances by these cells.According to the observations the above-mentioned oestrogen compound may be labelled with iodine isotope yielding gamma radiation which substance is deposited in the prostate and makes possible its scintigraphic examination. Uptake may be recorded in the so-called prostatic hypertrophic nodule, in malignant prostatic tumours, i.e. also in the bone and soft tissue metastases of the latter cases. Further intensive and detailed examinations are required to investigate the characteristic features of prostatic tumours.     

Breast malignancy in female-to-male transsexuals: systematic review,case report,and recommendations for screening

BackgroundFemale-to-male (FtM) transsexuals may use testosterone therapy for masculinization, which potentially influences the risk of breast cancer development. Guided by our case report, we aimed to investigate the evidence regarding the risk of testosterone therapy on breast malignancy in female-to-male transsexuals and evaluate breast cancer screening in this subgroup.MethodsWe conducted a systematic literature search according to the PRISMA checklist in June 2020 in PubMed/MEDLINE and Ovid/EMBASE. Reference lists of included articles were screened to find additional articles that met the inclusion criteria. All cohort studies and case reports evaluating breast cancer in FtM transsexuals after testosterone therapy were included.ResultsWe found 23 cases of FtM transsexuals who developed breast cancer after testosterone therapy, including our own case. Moreover, we evaluated ten retrospective cohort studies investigating breast malignancy in the transsexual population. The cohort studies showed no elevated risk in FtM transsexuals compared to natal women. Including our own case, nine cases were described in which breast malignancy was incidentally found during routine histological examination after mastectomy. High-level evidence for a correlation between testosterone therapy and breast malignancy is missing.ConclusionFew cases are described of FtM transsexuals with breast malignancy. However, cases such as these make physicians aware of the possibility of breast cancer in FtM transsexuals. Radiological screening of FtM transsexuals for breast cancer prior to mastectomy and histological screening of the mammalian tissue after mastectomy should be considered; physicians should decide together with every individual FtM transsexual if screening is necessary.     

Pilot study on liposomal recombinant human superoxide dismutase for the treatment of Peyronie's disease.

OBJECTIVE: To assess the efficacy and safety of liposomally encapsulated recombinant human superoxide dismutase (lrhSOD) for the treatment of Peyronie's disease. METHODS: In an uncontrolled phase-2 study, 20 patients with Peyronie's disease were treated with a gel containing lrhSOD (1.5 mg/g). Patients with penile deviation of >45 degrees or plaque calcifications of >5 mm were regarded as candidates for surgical correction and excluded from this study. RESULTS: Elimination of pain was observed in 7/13 patients (in 2 patients after only 3 days of therapy), and an almost complete resolution of pain was reported by the remaining 6/13 patients. Plaque size was reduced in 8/14 patients. Minimal improvement of penile deviation was observed in 3/12 patients. Post-therapeutic improvement of sexual function, mainly due to cessation of pain, was reported by 12/15 patients. No systemic or local side effects were observed. CONCLUSION: In the present study, 100% pain relief as well as a plaque size reduction in 56% of Peyronie's disease patients were observed after a maximum of 6 weeks of lrhSOD therapy. The convenience and safety of lrhSOD gel therapy were superior compared to other current regimens. The present results suggest that lrhSOD gel is a promising treatment for patients with early stage Peyronie's disease. Early institution of lrhSOD therapy may prevent disease progression to penile deviation. The present preliminary results are the basis of a placebo-controlled randomized study.     

Patients at high risk of cardiovascular complications in oestrogen treatment of prostatic cancer

The aim of this study was to predict cardiovascular complications in patients with prostatic cancer treated with oestrogen. A randomised prospective study of oestrogen therapy versus orchiectomy was performed. Patients with pre-existing cardiovascular morbidity were excluded (16%). Prior to the initiation of therapy, patients were subjected to exercise stress tests, physiological evaluation of peripheral circulation, blood volume estimation, chest X-ray, blood test, including hormones, lipoproteins, and antithrombin III, and a physical examination and history by a cardiologist. The oestrogen treatment and the orchiectomy group did not differ with regard to these pretreatment variables; 25% of the patients given oestrogen therapy had cardiovascular complications during the initial treatment year compared with none in the orchiectomy group. Three statistical discriminating techniques were employed and they allowed us to identify 2 strong discriminating variables for cardiovascular complications if oestrogen therapy is instituted in patients with prostatic cancer but without overt clinical cardiovascular disease. These 2 discriminators were luteinising hormone (LH) and ST-segment depression during exercise. This means that a patient with ST-segment depression during an exercise test and/or a high luteinising hormone concentration should not be treated with oestrogen.     

Characterization of secretion pattern of human prostatic acid phosphatase: a reassessment

The daily variation of serum levels of prostatic acid phosphatase (PAP) determined by the Roy enzymatic method was investigated in 10 patients with metastatic prostatic cancer and in 10 patients without prostatic disease. Duplicate serum samples were obtained from all patients on the same day at 8 AM, 12 PM, 4 PM, and 8 PM. Statistical analysis of the mean PAP levels at the four sampling times in both groups of patients demonstrated no evidence of circadian or diurnal rhythmic variation. Prostate cancer patients did show significantly greater variability in daily PAP than patients without prostatic disease, although a distinct pattern of secretion was not observed in either group. These results underscore the potential inaccuracy of the use of single determination of serum PAP as a parameter of response in patients with metastatic prostatic cancer and in the staging of patients with clinically localized prostatic malignancy. Evaluation of trends of PAP levels over time, however, continues to play a major role in the assessment and management of patients with prostatic carcinoma.     

Comparison of primary orchiectomy with oestrogen therapy in advanced prostatic cancer. A 2-year follow-up report of a national, prospective prostatic cancer study

Two hundred and seventy-seven patients with advanced prostatic cancer were treated by either orchiectomy or oestrogen. During the 2-year follow-up period, the response to treatment was considered more favourable in the oestrogen group, and this response was particularly emphasised in patients with poorly differentiated tumour and metastases at the time of diagnosis. Further evaluations included the cardiovascular side effects of oestrogen therapy.     

The cost of prostatic cancer in a defined population

Health-service costs for prostatic adenocarcinoma were calculated on the basis of 101 patients resident in the Link?ping area throughout their illness and who died in 1984-1985. At the time of diagnosis 54 tumours were advanced and 47 were localized. Primary treatment was expectant or surgical in 77 and oestrogen therapy in 17 cases. The average number of life-years lost was 4.3 in the total series and 10.7 in the men younger than 70. The median cost per case, SEK 50,000 (US dollars 7,900), was significantly lower than the average cost, SEK 79,000 (US dollars 12,400), due to a few high-cost patients. Approximately 50% of the total treatment cost was incurred during the year before death. The total number of hospitalizations for prostatic cancer in Sweden during 1984 was 11,800. The total estimated cost of this disease for the Swedish Health Services in 1985 was around 300 million SEK (47 million US dollars).     

Orchiectomy versus oestrogen in the treatment of advanced prostatic cancer

The primary clinical efficacy of orchiectomy and the combination therapy of intramuscular polyoestradiol phosphate 80 mg monthly and oral ethinyl oestradiol 0.15 mg daily was evaluated by progression and cancer mortality rates in a series of 277 prostatic cancer patients representing part of the Finnprostate study. After a follow-up of 5 years there was a significant difference between the groups in terms of progression rate and prostatic cancer deaths. The oestrogen combination was more effective in delaying progression of the disease. The overall mortality rate was similar in both groups. About one-third of the patients were alive after 5 years.     

Investigation of the antifibrotic effect of IFN-gamma on fibroblasts in a cell culture model of Peyronie's disease

OBJECTIVE: A broad spectrum of options is available for treatment of Peyronie's disease; however, the effects of minimally invasive therapy are generally inadequate. Although useful, oral drugs must be administered at onset of the disease. Only a few patients request penile surgery. Therefore, new medical treatments for Peyronie's disease are needed. A better understanding of the pathogenesis of Peyronie's disease is required to facilitate development of these new medical treatments. Several studies have described an increased level of TGF-beta in the fibrotic plaques of patients with Peyronie's disease, underscoring this important signalling pathway in the onset and/or development of Peyronie's disease. METHODS: Plaque biopsies were taken from 16 patients with Peyronie's disease. Furthermore, 7 patients without Peyronie's disease were biopsied to provide control material. Fibroblasts were cultured from biopsy tissue, and cultured fibroblasts were stimulated with TGF-beta1, BMP-2, IFN-gamma, and IFN-gamma combined with one of the other stimuli. Protein was extracted from treated fibroblasts and prepared for immunoblots. The membranes were probed for phosphorylated Smad and total Smad to indicate activation of TGF-beta signalling. RESULTS: An agonistic effect of IFN-gamma on TGF-beta signalling was observed. Stimulation with TGF-beta1 increased levels of phospho-Smad2 and phospho-Smad3. After stimulation with TGF-beta1 and IFN-gamma combined, the levels of phospho-Smads were higher than those observed with stimulation withTGF-beta1 alone. CONCLUSIONS: The profibrotic effect of TGF-beta1 is enhanced by IFN-gamma in fibroblasts from patients with Peyronie's disease. The inhibitory effects of IFN-gamma on the TGF-beta pathway do not appear in Peyronie's disease. Therefore, IFN-gamma cannot be taken as a useful tool in the therapy of Peyronie's disease.     

Aminoglutethimide in advanced prostatic carcinoma

We have treated 34 patients with advanced prostate cancer, resistant to orchiectomy or oestrogen therapy, with aminoglutethimide. Seven patients (21%) showed improvement in pain and performance status for prolonged periods. By NPCP criteria six patients had stable disease and one had partial tumour response. Six of these patients remained on oestrogen therapy. Suppressed gonadotrophin levels (FSH and LH), despite orchiectomy, correlated strongly with benefit from aminoglutethimide. No relationships between response to treatment and changes in serum testosterone, dehydroepiandrosterone, oestradiol or prolactin were found. Six patients had side effects requiring cessation of therapy. A further 27 patients developed less severe toxicity. Despite its toxicity, these results show that aminoglutethimide has a role in the management of advanced prostatic cancer resistant to primary hormonal manipulation.     

Efficacy of orchiectomy versus high dose polyoestradiol phosphate (160 mg) in relieving infravesical obstruction in patients with prostatic cancer

Post voiding residual urine volume (78 patients) and maximum urinary flow rate (59 patients) were measured in prostatic cancer patients treated by orchiectomy or oestrogen (polyoestradiol phosphate 160 mg i.m. monthly) to compare the effects of these endocrine treatments on bladder outlet obstruction caused by prostatic carcinoma. The relieving effect of orchiectomy seemed to be more apparent than that of high dose oestrogen during the first six months of therapy.     

Cardiovascular complications of estrogen therapy for nondisseminated prostatic carcinoma. A preliminary report from a randomized multicenter study

In a prospective multicenter study, 244 men with highly or moderately differentiated prostatic cancer in stage I, II or III (VACURG) were consecutively randomized to three groups of treatment: Group A (77 patients) received polyestradiol phosphate (Estradurin, Leo) 80 mg i.m. every fourth week + ethinyl estradiol (Etivex, Leo) 150 micrograms daily, group B (72 patients) estramustine phosphate (Estracyt, Leo) 280 mg twice daily, and group C (76 patients) no therapy. Only men without current or previous other malignancy and without cardiovascular disease were admitted to the study. After 4 1/2 years 125 of the 244 patients had left the study, 9 because of cancer progression (stage IV, VACURG). The most serious complications were cardiovascular, including ischemic heart disease, cardiac decompensation, cerebral ischemia and venous thromboembolism, which occurred in 24 patients from group A and 9 from group B as compared to only one patient in group C. The subgroup superficial or deep venous thrombosis comprised 11 group A and 2 group B patients. Estrogens (E + e) offered as palliative treatment to patients with non-generalized prostatic carcinoma is burdened with a high incidence of serious cardiovascular complications.     

Alterations in host responsiveness in patients with prostatic cancer following cryosurgery or transurethral resection.

Anesthesia, stress, trauma or the operation per se have been reported to result in alterations of host resistance in a wide range of diseases. The effect of such changes on the thymolymphatic system of patients with prostatic cancer is not known. While evaluating in vitro parameters of cellular immunologic responsiveness in patients with prostatic cancer, we have observed a depression two to seven days following cryosurgery or transurethral resection (TUR) of the proliferation of phytohemagglutinin (PHA)-stimulated peripheral blood lymphocytes (PBL). Contrary to the reduced proliferation of PBL cultured in autologous and homologous serum from patients receiving TUR, patients receiving cryosurgery, while also showing reduction in autologous serum, showed increased responsiveness when cultured in homologous serum. Although transient, depression of lymphocyte proliferation, particularly if involving tumor-cloned T-cells, may provide reduced surveillance to potential metastatic tumor cells leading to an alteration of tumor-host homeostasis. The potential of reduced surveillance, at least in the case of TUR, appears to be supported by observations that patients dying from prostatic cancer at our institution had an antecedent TUR. Identifying those patients with changes in responsiveness before surgery, as well as those prone to develop or undergo further reductions in responsiveness after surgery, would appear to be relevant in the management of patient with prostatic as well as other malignancies. Pre- and/or postoperative immunotherapy in such patients may be indicated.     

Reversibility of the effect of LHRH agonists and other antiandrogenic hormones on the testis: a histomorphometric study

Changes in testicular morphology are quantified in patients with metastatic prostatic cancer, treated with LHRH agonist Buserelin and compared with testes of young transsexuals and patients with metastatic prostatic cancer treated with orchidectomy only. No significant changes within 18 months were seen, suggesting reversibility of LHRH agonist effects on testicular morphology in this time period. Histomorphometrics of the testis are useful to quantify these changes.     

Serum proteins in prostatic cancer VI. Reduction of the suppressive ("blocking"?) properties of serum on in vitro parameters of cell-mediated immunologic responsiveness following cryosurgery.

Preliminary studies of sera from prostatic cancer patients have indicated a reduction in the presence of suppressive ('blocking'?) properties of in vitro parameters of cell-mediated immunologic responsiveness induced by a non-specific mitogen (phytohaemagglutinin) in association with a decrease in the level of alpha2-globulin and favourable clinical response following cryosurgery. The origin of the immunosuppression factor(s) migrating on electrophoresis in the alpha2-globulin fraction of serum remains to be identified. Earlier demonstration of suppression of leucocyte migration by factors elaborated from tumour cells and recent observations of the suppression of lymphocytic reactivity by seminal plasma and coaguloprostatic fluid suggest that suppression and reduction or abrogation of the suppressive properties of serum following cryosurgical destruction of tumour may be attributed to a reduction in soluble prostatic tumour-associated antigen shed into the circlation by previously viable tumour. Such antigen while not at a sufficient concentration to engender an immunologic response in the aging and tumour-burdened host, may, however, have been sufficient to pre-empt the effector limb of cell-mediated responsiveness contributing to the observed suppression of lymphocytic reactivity. Cryosurgery, resulting in necrosis and cell death with depletion of the primary source of antigen might thereby have permitted a previously overwhelmed host to respond, viz., the favourable clinical response observed.     

Development of androgen-independent tumor cells and their implication for the treatment of prostatic cancer

Summary Development of androgen-independent prostatic cancer cells from androgen-responsive cells can occur by a variety of mechanisms (e.g., environmental adaptation, multifocal origin, or genetic instability). Regardless of the mechanism of development, however, once androgen-independent cancer cells become present within prostatic cancer, the tumor is no longer homogeneous but is now heterogeneous. Once a prostatic cancer is heterogeneously composed of both androgen-dependent and-independent cancer cells, androgen withdrawal therapy, no matter how complete, cannot be curative. In order to produce cures of such heterogeneous prostatic cancers, hormonal therapy must be combined simultaneously with chemotherapy early in the course of the disease so that all the cancer populations (i.e., androgen-dependent and-independent) can be simultaneously affected within an individual patient.Part of this paper was presented at the 5th Congress of the European Society for Urological Oncology and Endocrinology, 18–20 August, 1986, Edinburgh, UK     

Computed tomography and transrectal ultrasound in the diagnosis of prostatic disease--a comparative study

Computed tomography (CT) and transrectal ultrasound were performed in 88 patients with clinically and histologically proven prostatic disease. An ultrasound diagnosis of prostatic cancer was suggested in 49 of 54 patients with proven disease, whereas CT identified only 21 of those patients. There were no specific features of confined prostatic malignancy on CT and the most reliable feature of an unconfined tumour was infiltration of the posterior aspect of the bladder base. It was not possible on ultrasound to differentiate between prostatic inflammatory disease and a confined carcinoma but ultrasound was accurate in detecting defects in the prostatic capsule, the hallmark of unconfined prostatic malignancy.