Biomedical subjects

E Huland

Publications and source records attributed to E Huland.

At least 37 records · Page 2Linked to original sources

PubMed2000

A comparison of systemic versus inhaled recombinant IL-2 administration for the treatment of metastatic renal cell carcinoma.

The aim of the current study was to compare the objective response and survival rates of patients with mRCC treated with IL-2 administered either systemically (SYST, subcutaneously) or via inhalation (INH), using relatively large sample sizes to afford a more meaningful comparison. We used univariate and multivariate analyses to retrospectively evaluate the data from two different databases generated from 277 patients treated with IL-2 during the 1993-1997 period, one developed at the University Hospital Hamburg-Eppendorf, and the other at Chiron-Amsterdam. Patients treated with INH IL-2 tended to have a poorer ECOG performance status than patients receiving SYST IL-2. Of 75 patients receiving INH IL-2, eight (10.7%) achieved an objective response; of 202 patients administered SYST IL-2, 45 (22.2%) achieved an objective response. The median survival time was 13.8 months for patients receiving INH IL-2 and 13.1 months for patients treated with SYST IL-2. One- and two-year survival rates were also comparable for the two treatment modalities (one-year: INH, 55%; SYST, 56%; two-year: INH, 28%; SYST, 26%). There was no significant difference in the likelihood of survival for patients receiving INH IL-2 versus SYST IL-2 (risk ratio = 0.82, P = 0.27). Patients administered INH IL-2 experienced considerably less toxicity and complications than patients administered SYST IL-2. We conclude that INH IL-2 treatment is at least as effective as SYST IL-2 treatment in promoting the survival of patients with mRCC. Given that INH IL-2 treatment of patients with a poorer ECOG performance status elicited a survival rate comparable to that seen with SYST IL-2 treatment of patients with a superior performance status, the potential exists for INH IL-2 treatment to be even more effective for patients having a better performance status. Additionally, INH IL-2 treatment is considerably less toxic and associated with fewer complications than SYST IL-2 treatment, thus providing a therapeutic option for otherwise untreatable patients, offering patients a relatively good quality of life, and requiring fewer co-medications. Nonetheless, selection of an IL-2 treatment modality should be based on several patient-related considerations. Moreover, these two IL-2 treatment modalities need not be mutually exclusive.

Administration, Inhalation↗

PubMed2000

Overview of interleukin-2 inhalation therapy.

PURPOSE: Locoregional administration of interleukin (IL)-2, which acts physiologically as a local hormone, is an effective therapeutic modality. Diverse preclinical and clinical models have described methods of administration that expose tumor tissues to continuously high levels of cytokines. Regional administration of IL-2 that does not raise intravascular IL-2 levels induces local and systemic immunomodulation and produces objective local tumor responses. Most importantly, regional therapy is much less toxic than systemic IL-2 therapy. PATIENTS AND METHODS: We review clinical experiences using inhaled IL-2 therapy for the treatment of pulmonary metastases in roughly 300 patients with a variety of primary tumors. This includes our own 10-year single-institution experience with inhaled IL-2 therapy in the treatment of 188 metastatic renal cell carcinoma patients with progressive pulmonary metastases. Patients in our clinic are treated with 18 to 36 million IU of recombinant IL-2, administered 90% by inhalation and 10% subcutaneously, until disease progression. A variety of doses and schedules of inhaled IL-2 have been investigated alone and in combination with systemic therapies. RESULTS: Inhalation of IL-2 has been reported to prevent progression of pulmonary and mediastinal metastases of metastatic renal cell carcinoma, breast and ovarian carcinoma, and melanoma. Inhaled IL-2 alone is well tolerated; a dose-dependent cough is the major adverse event. A significant dose-dependent increase in lymphocytes and eosinophils has been observed in bronchoalveolar lavage in patients and animals. Dose and schedule can influence outcome. In a phase I trial using inhaled IL-2 alone in patients with a variety of primary malignancies, once-daily inhalation of IL-2 at doses up to 15 million IU/m2 was well tolerated but did not result in prolonged stabilization of pulmonary disease. In a multidose phase I trial, using 5-times-daily inhalation of natural IL-2, pulmonary lesions in three of 14 (21%) metastatic renal cell carcinoma patients responded, and a similar multicenter trial demonstrated a 29% response rate. Among 188 metastatic renal cell carcinoma patients treated with inhaled recombinant IL-2 at the Clinic Eppendorf, progression of pulmonary metastases was prevented in 68% of patients for a median duration of 7 months, and overall survival was significantly improved compared with expected survival (Elson's risk analysis; 17.2 vs 5.3 mo). All patients, including high-risk patients, appeared to benefit. Encouraging results have also been reported in patients with metastatic melanoma and gynecologic tumors when inhaled IL-2 was used as second-line therapy to treat pulmonary metastases. CONCLUSIONS: The efficacy of inhaled IL-2, alone or in combination with systemic immunotherapy, immunochemotherapy, or chemotherapy, has been documented in a variety of malignancies. All reports confirm low toxicity, thus providing important quality-of-life benefits. Moreover, patients not eligible for systemic IL-2 therapy may be treated with inhalation therapy.

Administration, Inhalation↗

PubMed2000

Detection of loss of heterozygosity in the p53 tumor-suppressor gene with PCR in the urine of patients with bladder cancer.

PURPOSE: Detection of loss of heterozygosity (LOH) has been described in various carcinomas on the basis of meticulous molecular techniques. Because of lack of simple and rapid techniques, LOH has not achieved common use in routine tumor diagnosis. A recently found variable number of tandem repeats (VNTR) segment in intron 1 of the p53 gene was described as highly polymorphic and therefore useful in detecting LOH. We used a rapid technique for detection of LOH in the p53 gene of patients with transitional cell carcinoma (TCC) of the bladder. The technique was based on the polymerase chain reaction (PCR) and agarose gel electrophoresis as described for other carcinomas previously. We evaluated whether TCC screening and surveillance could be performed detecting LOH in the urinary sediment. MATERIALS AND METHODS: We investigated 29 patients with TCC of the bladder (pTa 12 patients; pT1 10 patients; pT2 - pT4 seven patients; grade 1 one patient; grade 2 19 patients; grade 3 nine patients). DNA was prepared by standard methods from white blood cells, tumor tissue, normal bladder mucosa, and urinary sediments. The amplification of the VNTR region was performed with PCR. PCR products were run in parallel lanes on 4.5% agarose gels. RESULTS: Of the 29 patients, 23 (79.3%) were found to have two different alleles ("informative cases") for the VNTR region. Of the 23 informative cases LOH was detected in the tumor tissue of 10 patients (43.5%). Referring to the total population 10 of 29 patients (34.4%) revealed LOH. In all patients with LOH in the tumor, LOH was also detected in the urinary sediment. LOH was not detected in the histologically benign bladder mucosa. CONCLUSION: We present a simple and rapid technique based on PCR and agarose gel electrophoresis for the detection of LOH in tumor and urinary sediment of patients with TCC of the bladder. The ability to detect LOH not only in tumor tissue but also in urinary sediment offers an attractive approach for noninvasive diagnosis and surveillance of bladder cancer patients.

Carcinoma, Transitional Cell↗

PubMed1999

[Treatment of pulmonary metastases from kidney cell carcinoma with inhalational interleukin-2. 10-year experience Hamburger Unicenter].

Systemic immunotherapy, notably with interleukin-2 (IL-2) and interferon-alpha (IFNalpha), has yielded a response rate of 10 % to 30 % in metastatic renal cell carcinoma. However, systemic immunotherapy is limited by severe side effects, and long-lasting response is rare. Tumor palliation and quality-of-life are important end points for evaluating the clinical benefits of immunotherapy. Experimental and clinical treatment models have proved that local IL-2 application is less toxic than systemic treatment and is therapeutically effective. Here we report long-term experience with inhalation IL-2 therapy in 188 patients who had progressive pulmonary metastatic renal cell carcinoma. High-dose inhalation of IL-2 was used with low-dose systemic IL-2 or IFNalpha. Maximal toxicity over the total treatment time was mild, and the low incidence of WHO grade 3 toxicity (24 %) allowed social activities and performance of social roles. Comedication for systemic side effects was required only in half of the patients. Inhaled IL-2 prevented progress of pulmonary metastases in 68 % of patients for a median period of 9.8 months. Median survival was 12.4 months compared with the expected 5.3 months and quality-of-life did not differ substantially from pretreatment status. Local treatment can be applied alone or in combination with systemic therapy and can increase therapeutic efficacy.

Administration, Inhalation↗

PubMed1999

Significance and metabolism of complexed and noncomplexed prostate specific antigen forms, and human glandular kallikrein 2 in clinically localized prostate cancer before and after radical prostatectomy.

PURPOSE: We studied plasma concentrations and elimination rates of prostate specific antigen (PSA) complexed to alpha1-antichymotrypsin and alpha2-macroglobulin, free PSA, total PSA (free PSA plus PSA alpha1-antichymotrypsin) and human glandular kallikrein 2 before, during and after radical retropubic prostatectomy for clinically localized prostate cancer. MATERIALS AND METHODS: Plasma was collected and frozen within 10 minutes after sampling from 18 patients undergoing radical retropubic prostatectomy for prostate cancer. One sample was drawn preoperatively. Subsequent sampling intervals were 5 to 20 minutes perioperatively, 2 to 4 hours during the first 12 postoperative hours and 24 to 48 hours until postoperative day 14. Free PSA, PSA alpha1-antichymotrypsin, total PSA, PSA alpha2-macroglobulin and human glandular kallikrein 2 were measured with time resolved immunofluorometric assays. RESULTS: Preoperatively PSA alpha2-macroglobulin was undetectable (less than 2 ng./ml.) in 17 of 18 patients. Human glandular kallikrein 2, free PSA and total PSA but not PSA alpha1-antichymotrypsin were significantly higher in patients with extraprostatic cancer (pT3a-pT4a, pN1) compared to those with organ confined cancer (pT2a/b). Surgical manipulation of the prostate caused no detectable elevation of human glandular kallikrein 2, PSA alpha1-antichymotrypsin or PSA alpha2-macroglobulin. In contrast, a mean 9.6-fold increase (range 3.4 to 22) in free PSA was noted 5 minutes after prostatectomy. Free PSA was eliminated from plasma in a biphasic exponential pattern with an early plasma half-life of 55 minutes and a late plasma half-life of 18 hours. PSA alpha1-antichymotrypsin decreased slowly, whereas human glandular kallikrein 2 was detectable only 12 hours after prostatectomy. PSA alpha2-macroglobulin remained at insignificant, nondetectable concentrations during the entire perioperative and postoperative period. CONCLUSIONS: Release of free PSA contributes to the elevation of plasma total PSA after prostatectomy. Free PSA is enzymatically inactive as the release does not result in subsequent elevation of PSA alpha1-antichymotrypsin or PSA alpha2-macroglobulin. Biphasic exponential elimination of free PSA may be explained by rapid extracellular redistribution (early half-life) and glomerular filtration in the kidneys (late half-life). Our data suggest rapid metabolism of human glandular kallikrein 2 but do not support suggestions of the significance in vivo of complex formations with alpha2-macroglobulin as a major means to eliminate PSA from plasma in patients with clinically localized prostate cancer.

Aged↗

PubMed1999

Early prostate-specific antigen relapse after radical retropubic prostatectomy: prediction on the basis of preoperative and postoperative tumor characteristics.

OBJECTIVES: This study was undertaken to distinguish between patients who will and will not benefit from a retropubic radical prostatectomy (RRP) for clinically localized prostatic carcinoma (PCa) on the basis of preoperative and postoperative tumor characteristics. METHODS: Data of 318 consecutive patients who underwent RRP for clinically localized PCa were reviewed. Preoperative characteristics used included clinical stage, findings on transrectal ultrasonography, prostate-specific antigen (PSA) values, Gleason grade, number of positive biopsies, number of biopsies containing any Gleason grade 4 and/or 5 cancer, and number of biopsies with predominant (>50% of cancerous tissue) Gleason grade 4 and/or 5 cancer. Postoperative characteristics included pathologic stage, Gleason grade, margin status, cancer volume, and volume of Gleason grade 4 and/or 5 cancer. The impact on biochemical relapse after RRP were calculated by Cox regression and CART (classification and regression tree) analysis to establish low, intermediate, and high risk of recurrence. RESULTS: Of patients who underwent RRP, 66% showed no evidence of relapse after a follow-up of 42 months. All preoperative and postoperative characteristics showed a significant association with biochemical relapse. Cox regression of preoperative characteristics showed the number of positive biopsies with predominant Gleason grade 4 and/or 5 cancer to be the most accurate predictor of failure (p < 0.0001), followed by the number of positive biopsies and PSA. CART analysis distinguished between four risk groups on the basis of the same characteristics as in the Cox regression. The low-risk group consisted of 232 patients (75.1%) and the high-risk group of 17 patients (5.5%); corresponding Kaplan-Meier curves showed a 2-year PSA-free survival rate of 97% for the low-risk group and 20% for the high-risk group. Cox regression of postoperative characteristics recognized the volume of Gleason grade 4 and/or 5 as the characteristic with the strongest association with biochemical failure. CART analysis distinguished between four risk groups, using the volume of high-grade cancer as the most influential characteristic. The corresponding Kaplan-Meier curves showed for the low-risk group (n = 79; 29.6%) a PSA-free survival rate of 96% after 42 months and for the high-risk group (n = 47; 17.6%) a 21% PSA-free survival rate after 42 months. CONCLUSION: For preoperative and postoperative estimation of biochemical recurrence after RRP, a quantitative analysis of high-grade cancer, expressed by the number of preoperative biopsy cores containing high-grade cancer and the volume of cancer, proved to be the best predictor of relapse. CART analysis might be useful in advising patients for their best therapy options. However, defined characteristics of risk groups should be evaluated with new prospective data before they are used routinely.

Adenocarcinoma↗

PubMed1999

Subjective and objective prospective, long-term analysis of quality of life during inhaled interleukin-2 immunotherapy.

PURPOSE: We conducted both a subjective and objective, prospective quality-of-life analysis during high-dose (36 x 10(6) immunizing units/d) inhalational interleukin (IL)-2 treatment (mean treatment time, 13.4 months) of 15 patients with metastatic renal cell carcinoma (mRCC). Additionally, quality of life for 10 patients with mRCC receiving low-dose (9 x 10(6) IU/m(2)/d for 5 days) intravenous IL-2 treatment also was evaluated. PATIENTS AND METHODS: Patients responded to the European Organization for Research and Treatment of Cancer quality-of-life questionnaire QLQ-C30 before and during inhalational IL-2 treatment at 1, 3, 6, 9, and 12 months and before and once during intravenous IL-2 treatment. A clinician assessed patient well-being using the Quality of Well-Being scale to calculate once weekly quality-adjusted life-years (QALYs) during inhalational IL-2 treatment. RESULTS: Patients completed 103 questionnaires and clinicians performed 892 QALY calculations. For patients treated with inhalational IL-2, the mean quality-of-life score deteriorated modestly but significantly 1 month after treatment initiation (15.1%, P =.01) but did not differ significantly from pretreatment scores after 3, 6, 9, and 12 months of treatment. Inhalational IL-2 therapy stabilized patient quality of life for a mean of 13.4 months. The resulting QALY calculation for patients on inhalation IL-2 was 70.1% of 13.4 months, representing 9.4 months of QALY. In comparison, patients who received intravenous IL-2 showed a more marked, statistically significant deterioration in mean quality-of-life score during treatment (27%, P =.006); moreover, three of these 10 patients experienced treatment-related toxicity that prevented questionnaire completion. CONCLUSION: Quality-of-life analysis during immunotherapy provides valuable information regarding cancer treatment outcomes.

Activities of Daily Living↗

PubMed1999

Ultrasensitive detection of prostate specific antigen in the followup of 422 patients after radical prostatectomy.

PURPOSE: We validated our ultrasensitive prostate specific antigen (PSA) assay based on lyophilization and 4-fold concentration of patient sera with the clinical long-term followup and according to histopathological characteristics of 422 patients treated with radical retropubic prostatectomy for prostate cancer. MATERIALS AND METHODS: Each serum sample was divided into 2 aliquots for standard and 4-fold concentrated (ultrasensitive) detection. Samples were analyzed by the same unmodified DPC-Immulite PSA assay. Biochemical relapse was defined as an increase of at least 0.10 ng./ml. in native serum (equivalent to 0.025 ng./ml. in concentrated serum). Mean followup was 449 days (range 29 to 2,057). Kaplan-Meier analysis of standard and ultrasensitive detection results was done, and findings were correlated with pathological stage, Gleason grade, total cancer volume, Gleason grade 4 cancer volume and margin status. Significance of earlier detection in ultrasensitive versus standard detection was calculated with the log rank (Mantel-Cox) test with p <0.05 considered significant. RESULTS: Of 442 patients 88 (20.8%) experienced biochemical recurrence. Of this cohort 28 (31%) demonstrated early failure on the ultrasensitive assay which was later confirmed on the standard assay, 37 (42%) had failure simultaneously on both assays and 23 (26%) had failure on the ultrasensitive but remained disease-free on the standard assay. Average time for ultrasensitive assay detection of recurrence was 288 days (standard 555). Kaplan-Meier analysis revealed significant advantages in earlier detection of recurrence with the ultrasensitive assay, and close correlation with pathological stage, Gleason grade, margin status and Gleason grade 4 cancer volume. Time advantages of ultrasensitive versus standard detection were greater for advanced cancers (pT3a/b or greater, Gleason 3 + 4 or greater) than for small, low grade tumors. All patients who had positive results on the standard assay had a previous (28) or simultaneous (37) positive ultrasensitive result. With standard detection 25% of all relapses were evident within the first year of surgery and with ultrasensitive detection the percentage increased to 85.7%. On both assays 334 patients remained free of biochemical recurrence. CONCLUSIONS: Our ultrasensitive PSA assay is useful for early detection of biochemical relapse after radical retropubic prostatectomy. It not only provides the same accuracy as conventional PSA assays but also offers the advantage of detecting recurrence about 300 days earlier. Thus, long-term results of radical retropubic prostatectomy series can be calculated sooner. The clinical impact of this assay will be obvious once curative treatment options are available if applied at the earliest time of evident tumor recurrence.

Follow-Up Studies↗

PubMed1999

Immunotherapy of pulmonary metastatic renal cell carcinoma: success dependant on risk factors?

BACKGROUND/AIMS: Risk factors may influence not only prognosis in metastic renal cell carcinoma but also probability of response to immunotherapy. Response of patients treated with inhalation of interleukin-2 (IL-2), which can be offered to those not suitable for systemic therapy, was compared to risk factors. We report on 116 patients who used inhaled IL-2 and were treated in different protocols with natural, recombinant glycosylated and recombinant non-glycosylated. METHODOLOGY: All protocols had in common a high-dose inhalation of IL-2, either exclusively (11%), with low-dose systemic IL-2 (33%), or with low-dose systemic IL-2 and interferon-alpha (56%). Maximal toxicity per total treatment time (median treatment time: 7.2 months) was mild and there was a low incidence (16%) of WHO grade 3 toxicity. Treatment response was analyzed in a subgroup of patients having at least one given risk factor and treated with recombinant IL-2 (n=86). In all patients having risk factors the following distribution was found: more than 1 metastic location (86%), diagnosis to treatment interval (DTI) <12 months (62%), weight loss prior to therapy (41%), and ECOG performance status > or =2 (13%). In comparison, a group of patients having no risk factors at all was analyzed accordingly. RESULTS: Response to immunotherapy is dependant on risk factors, the most prominent one being the ECOG. Patients with an ECOG > or =2 achieved no overall response compared to patients with no risk factors who responded to immunotherapy (33%). Progressive pulmonary metastases responded in 15% of patients for a median of 15.5 months (range: 4.133) and were stabilized in 55% for a median of 6.6 months (range: 3-51.7). Overall response rate was 16%, 49%, and 35%, respectively. Median overall response duration was 9.6 months. Median achieved survival was 11.8 months (range: 1.7-68.8). CONCLUSIONS: We conclude that risk factors have to be considered in the interpretation of response to immunotherapy. Exclusion of patients because of risk factors alone does not seem to be justified according to our data. Responses, including long-term stabilization, can be achieved in 27-57% of such patients. IL-2 immunotherapy can also be considered as useful antitumor therapy in patients with risk factors, especially if given without major toxicity.

Administration, Inhalation↗

PubMed1998

The value of the ratio of free-to-total prostate specific antigen for staging purposes in previously untreated prostate cancer.

PURPOSE: We analyzed the use of the ratio of free-to-total prostate specific antigen (PSA), also termed percentage of free PSA, for predicting tumor stage, volume and grade in patients with clinically localized prostate cancer. MATERIALS AND METHODS: A total of 515 consecutive patients underwent further prostate evaluation due to elevated PSA (greater than 4.0 ng./ml.) or abnormal digital rectal examination. Prostate cancer was diagnosed in 307 patients (59.6%), including 170 (55.4%) who underwent radical retropubic prostatectomy. Data on pathological stage, Gleason grade, and total and Gleason grade 4 cancer volume were available in all patients. In the remaining 208 men (40.4%) benign prostate hyperplasia was diagnosed. Total and free PSA was measured in preoperative serum. RESULTS: Total PSA was significantly higher (p <0.0001) in the 71 men with stage pT3 tumors than in the 91 with pT2 disease. Eight patients had stage pT4 tumors. Cancer volume correlated well with advancing pathological stage (p <0.0001) and total PSA (p <0.0001). The free-to-total PSA ratio was not significantly different (p = 0.93) in stages pT2 and pT3 tumors, and it did not correlate with total (p = 0.71) or pure Gleason grade 4 (p = 0.94) cancer volume. However, the ratio of free-to-total PSA tended to decrease (p = 0.07) in tumors of increasing Gleason grade. CONCLUSIONS: The ratio of free-to-total PSA does not help in the preoperative prediction of final tumor stage and volume. However, disease grading may alter the free-to-total PSA ratio.

Biomarkers, Tumor↗

PubMed1998

Incidence of positive surgical margins after biopsy-selected nerve-sparing radical prostatectomy.

OBJECTIVES: The selection criteria for a nerve-sparing radical prostatectomy (NSRP) are not thoroughly investigated and are based mainly on preoperative digital rectal examinations and intraoperative findings. At our institution NSRP is performed only on patients whose preoperative systematic sextant biopsy of the prostate showed only unilateral cancer. To prove the safety of these criteria, we analyzed the incidence of positive surgical margins and tumor progression rate in patients who were selected for an NSRP only by the result of the biopsy. METHODS: Preoperative systematic sextant biopsies revealed unilateral cancer in 69 preoperatively potent men of 289 consecutive prostatic cancer patients (23.9%); contralateral NSRP was performed on these 69 patients. The prostate specimens were investigated by using a 3-mm step-section technique to identify positive surgical margins. Tumor progression was defined as a prostate-specific antigen (PSA) level greater than 0.4 ng/mL in the native and greater than 0.025 ng/mL in the suprasensitive postoperative blood test. Mean follow-up was 15 months (range 6 to 24). RESULTS: In 69 patients who underwent NSRP, 11 positive margins (15.9%) were found. Only 3 patients (4.3%) had a positive margin on the nerve-sparing side. In 220 patients who underwent non-NSRP 59 positive margins (26.8%) were detected. PSA recurrence rate after 12 months was similar in patients with NSRP and non-NSRP. Analysis of systematic sextant biopsies gives safe selection criteria because in approximately 95% the surgical margin on the nerve-sparing side will be negative. CONCLUSIONS: Basing the indication for an NSRP on the results of preoperative systematic biopsies was safe according to margin status and postoperative PSA, when all patients with tumor in one of the three biopsy cores of each side of the prostate were excluded from an NS technique on that side. Such a strict approach will exclude approximately 30% of patients from NSRP unnecessarily because of tumor findings on a prostate side where the cancer is still organ-confined. Less strict criteria, including patients with only well-differentiated cancer and a maximum of one positive biopsy on the evaluated side, seem to be as safe as the described selection. However, data on these patients need further evaluation.

Aged↗

PubMed1997

Intratumoral depot interleukin-2 therapy inhibits tumor growth in Dunning adenocarcinoma of the prostate implanted subcutaneously in rats.

The purpose of this study was to determine the effectiveness and toxicity of local continuous immunotherapy of prostatic cancer. A group of 60 young male Copenhagen rats with Dunning adenocarcinoma of the prostate, implanted subcutaneously into both flanks, after proven tumor growth, were treated with either human interleukin-2 (IL-2) depot preparations (n = 30) or albumin (placebo) depot preparations (n = 30) implanted directly into one tumor site. IL-2 depots released IL-2 reliably for more than 24 days. The rat serum was tested during treatment for human IL-2, possibly absorbed from depots, and for rat interferon gamma. IL-2 treatment reduced tumor growth significantly (P < 0.001) compared with albumin-treated sites or untreated contralateral sites. No toxicity was observed during treatment. Neither human IL-2 nor rat interferon gamma was detected in the serum, which indicates an exclusively local IL-2 effect. IL-2 depot preparations reduce tumor growth in Dunning adenocarcinoma of the prostate significantly without toxicity.

Adenocarcinoma↗

PubMed1997

Prostatic volume and ratio of free-to-total prostate specific antigen in patients with prostatic cancer or benign prostatic hyperplasia.

PURPOSE: We correlated prostatic volume with the ratio of free-to-total prostate specific antigen (PSA) in serum from patients with prostatic cancer or benign prostatic hyperplasia (BPH) to evaluate how prostatic volume influences the ratio. MATERIALS AND METHODS: We evaluated sera from 395 patients (mean age 65 years, range 45 to 88) with prostate cancer (239) or BPH (156) for total PSA, free PSA and ratio of free-to-total PSA. For detection of total and free PSA we used an Immulite free and total PSA assay. Prostatic volume was determined with transrectal ultrasonography. Prostatic volume in BPH and prostate cancer patients was divided into 10 ml. groups, and mean ratio of free-to-total PSA was calculated for each volume group and both diseases. For statistical analysis Mann-Whitney U and Kruskal-Wallis tests were performed in addition to calculation of sensitivity and specificity, and receiver operator curves for prostates 60 ml. or less and greater than 60 ml. RESULTS: For BPH patients the mean ratio of free-to-total PSA was 14.64 to 25.14% without a close relation to prostatic volume. In prostate cancer patients a proportional increase from 8.45 to 19.37% in the ratio of free-to-total PSA with volume was found. Mann-Whitney U analysis revealed significant differences in prostate cancer versus BPH only in patients with prostates of 60 ml. or smaller (p = 0.0008 to 0.029). No significant differences were seen when prostate cancer and BPH patients with prostates larger than 60 ml. were compared (p = 0.082 to 0.868). Kruskal-Wallis test confirmed independence of the ratio of free-to-total PSA from prostatic volume in BPH patients (p = 0.285) but dependence in prostate cancer patients (p <0.0001). Sensitivity was higher in patients with prostates 60 ml. or smaller (86.72%) than in patients with prostates larger than 60 ml. (66%), and specificity was lower at 45.78 and 56.16%, respectively. CONCLUSIONS: We have shown that the ratio of free-to-total PSA is influenced by prostatic volume in patients with prostate cancer. The ratio of free-to-total PSA provides useful information for differentiate BPH from prostate cancer in patients with small prostates but it is less useful in patients with larger prostates, probably because of the larger proportion of benign hypertrophic tissue.

Aged↗

PubMed1997

Use of serum concentration techniques to enhance early detection of recurrent prostate cancer after radical prostatectomy.

OBJECTIVES: We evaluated the clinical applicability of serum concentration techniques to enhance the detection of prostate-specific antigen (PSA) in men with recurrent prostate cancer after radical prostatectomy. METHODS: We concentrated blood serum by lyophilization and ultrafiltration from female patients who had undergone cystoprostatectomy, "cured" patients who had undergone radical prostatectomy, patients without prostate cancer, and patients with prostate cancer treated with radiation or hormonal therapy. The primary study group consisted of 31 patients with recurrent disease after radical prostatectomy whose initial postoperative PSA fell to undetectable levels (less than 0.07 ng/mL) that later turned positive (0.07 ng/mL or more) by the Tosoh AIA 600 immunoassay run in the ultrasensitive mode. All serum samples of less than 0.07 ng/mL were concentrated by lyophilization or ultrafiltration. RESULTS: Serum concentrated by lyophilization and filtration detected PSA recurrence significantly earlier than did unconcentrated serum in 29 of 31 patients (94%) and in 28 of 31 patients (90%), respectively. The mean advantage for the 29 patients was 362 days; for the 28 patients it was 383 days. The mean native PSA was 0.04 ng/mL (range 0.00 to 0.06) at the time of earliest detection by concentration techniques. Serum from female patients who had undergone cystoprostatectomy and "cured" patients who had undergone radical prostatectomy failed to concentrate, giving a test specificity of 100%. CONCLUSIONS: Serum concentration is a specific and sensitive technique that provides a significant lead time of an additional 12 months in detecting cancer recurrence after radical prostatectomy when compared with nonconcentrated serum. Because the Tosoh assay, when run in the ultrasensitive mode, gave an additional lead time of 9 months at a residual cancer detection limit of 0.07 ng/mL, the combination of the Tosoh assay and serum concentration allows detection of a failed radical prostatectomy about 2 years earlier than does the Hybritech Tandem-R assay, which has a residual cancer detection limit of 0.2 ng/mL.

Aged↗

PubMed1997

Tumor-associated antigens in normal mucosa of patients with superficial transitional cell carcinoma of the bladder.

PURPOSE: We identified premalignant lesions in tumor-surrounding histologically normal bladder mucosa from patients with superficial and muscle-invasive bladder cancer to look for "premalignant" lesions as the source of tumor recurrence. MATERIALS AND METHODS: Tumor-associated antigen expression in histologically normal bladder mucosa in 23 patients with superficial bladder cancer was studied. Histologically normal bladder specimens from 21 patients with muscle-invasive bladder cancer and from 30 prostatic cancer patients served as controls. Tumor-related antigens 486p 3/12, LBS8, 19A211 and M344 were mapped quantitatively with monoclonal antibodies and immunohistological techniques. RESULTS: Expression of all four bladder tumor-associated antigens was significantly enhanced and more than two antigens were expressed simultaneously in histologically normal mucosa from both bladder-cancer groups, compared with histologically normal bladder mucosa of prostatic carcinoma patients (p < 0.05). CONCLUSIONS: The results suggest the existence of early malignantly transformed cells in the benign-looking and morphologically normal bladder mucosa of superficial bladder carcinoma patients, which possibly is the source of recurrent bladder cancer. This approach models the mapping of histopathologic premalignant lesions of the bladder to predict risk.

Aged↗

PubMed1997

Inhaled interleukin-2 therapy in pulmonary metastatic renal cell carcinoma: six years of experience.

PURPOSE: Patients with advanced metastatic renal cell carcinoma often cannot or do not want to tolerate high-dose systemic interleukin-2 (IL-2) therapy and the toxicity associated with it. To reduce toxicity and still maintain or even increase effectiveness, we developed a method to deliver IL-2 locally for the treatment of pulmonary and mediastinal metastases in metastatic renal cell carcinoma patients. PATIENTS AND METHODS: We report here 6 years of experience treating 116 metastatic renal cell carcinoma patients who had pulmonary or mediastinal metastases with inhaled IL-2. We have utilized three different IL-2 preparations (natural human IL-2 purified from the supernatants of mitogen-activated peripheral blood lymphocytes, glycosylated recombinant IL-2 produced by Chinese hamster ovary cells, and non-glycosylated recombinant IL-2 produced by bacteria). All protocols used high-dose inhalation of IL-2, either exclusively (11%), with coadministration of low-dose systemic IL-2 (33%), or with coadministration of low-dose systemic IL-2 and interferon-alpha (56%). RESULTS: Maximal toxicity per total treatment time was mild (median treatment time, 7.2 months); there was a low incidence (16%) of World Health Organization grade 3 toxicity. Toxicity associated with exclusive inhalation of IL-2 was local and consisted mainly of cough. Thus, patients who could not tolerate high-dose systemic IL-2 were able to tolerate inhalation IL-2 therapy. Progressive pulmonary metastases responded in 15% of patients for a median of 15.5 months (range, 4.1-33 months) and were stabilized in 55% of patients for a median of 6.6 months (range, 3-51.7 months). The overall response rate was 16%; disease was stabilized in 49% of patients and disease progressed in 35% of patients. The overall median response duration was 9.6 months. Median survival was 11.8 months (range, 1.7-68.8 months); expected survival according to risk analysis was 5.3 months. CONCLUSIONS: Inhalation of IL-2 is a nontoxic and effective treatment for patients with progressive pulmonary and mediastinal metastases. Inhaled IL-2 effectively prevented progress of pulmonary metastases in 70% of patients. Furthermore, patients could be treated as outpatients and remain employed. Local administration of IL-2 increases therapeutic effectiveness with little or no toxicity.

Administration, Inhalation↗

PubMed1996

Preoperative prediction of tumor heterogeneity and recurrence after radical prostatectomy for localized prostatic carcinoma with digital rectal, examination prostate specific antigen and the results of 6 systematic biopsies.

PURPOSE: Digital rectal examination, preoperative serum prostate specific antigen (PSA) concentration and results of 6 ultrasound guided systematic sextant biopsies in 257 consecutive patients with clinical stages T2 and T1c prostatic carcinoma were evaluated for their use in predicting pathological stage and tumor recurrence. MATERIALS AND METHODS: Each of the 257 consecutive specimens was examined using the 3 mm. step section technique. Results of preoperative digital rectal examination, PSA and 6 systematic sextant biopsies were correlated with pathological stage, margin status and postoperative PSA during a mean followup of 2 years. Patients were considered to have disease progression based on elevated PSA level by a supersensitive assay. RESULTS: Digital rectal examination could not predict pathological stage and tumor recurrence. Preoperative PSA concentration, number of positive biopsies and tumor grade in the biopsy specimens correlated well with pathological stage. The best predictor of tumor recurrence was the biopsy result. However, a precise prediction of outcome (87% probability of being PSA negative versus 0%) was possible only in a third of the patients if the biopsy results were used. Use of preoperative PSA concentration did not improve this probability. CONCLUSIONS: Preoperative PSA concentration and/or biopsy results correlate significantly with pathological stage and margin status. Precise prediction of tumor recurrence is possible in only approximately a third of the patients with clinical stage T2 prostatic carcinoma.

Aged↗

PubMed1996

Phase I trial of inhaled natural interleukin 2 for treatment of pulmonary malignancy: toxicity, pharmacokinetics, and biological effects.

Safety, local and systemic immunomodulation, and tumor response to treatment with aerosolized natural interleukin 2 (nIL-2) applied five times a day were studied in a Phase I trial in 16 patients with pulmonary malignancies refractory to conventional therapy. The toxicity of inhaled nIL-2 was different from that observed after systemic administration. Reversible airway irritation causing a nonproductive cough represented the dose-limiting toxicity. Mild to moderate reduction of the vital capacity and forced expiratory volume (FEV1) with minor effects on relative FEV1, peak expiratory flow, airway resistance, and PaO2 was experienced by individual patients. In 14 patients suffering from pulmonary metastases due to renal cell cancer, one durable complete response, one partial response, and one mixed response were observed. Inhalation of nIL-2 aerosol resulted in a dose-dependent expansion of pulmonary immunocompetent cells in bronchoalveolar lavage fluid. Posttreatment bronchoalveolar lavage showed an activated lymphocyte phenotype with increased HLA-DR expression. The only systemic biological effect detectable in peripheral blood was a marked increase of soluble interleukin 2 receptor serum levels. We conclude that treatment with aerosolized nIL-2 is an effective means for site-specific immunomodulation and deserves further investigation for the treatment of malignant and inflammatory lung disease.

Administration, Inhalation↗