Biomedical subjects
Publications and source records attributed to S L Goldenberg.
We describe a case of testicular pseudotumor evaluated with both diagnostic ultrasound (US) and magnetic resonance (MR) imaging. The findings were inconclusive and eventually radical orchiectomy and pathologic analysis were required to make the diagnosis. The typical US and MR findings of both inflammatory and neoplastic lesions of the testis are discussed.
OBJECTIVES: To test the feasibility of using intermittent androgen suppression in the treatment of prostate cancer by taking advantage of the reversible action of medical castration. METHODS: Observations were made on a group of 47 patients (clinical Stage D2, 14; D1, 10; C, 19; B2, 2; and A2, 2) with a mean follow-up time of 125 weeks. Treatment was initiated with combined androgen blockade and continued for at least 6 months until a serum prostate-specific antigen (PSA) nadir was observed. Medication was then withheld until the serum PSA increased to a mean value between 10 and 20 ng/mL. This cycle of treatment and no treatment was repeated until the regulation of serum PSA became androgen independent. RESULTS: The first two treatment cycles lasted 73 and 75 weeks, with a mean time off therapy of 30 and 33 weeks and an overall mean percentage time off therapy of 41% and 45%, respectively. The mean time to achieve a nadir level of serum PSA was 20 weeks in cycle 1 and 18 weeks in cycle 2. Serum testosterone returned to the normal range within 8 weeks (range, 1 to 26) of stopping treatment. The off-treatment period in both cycles was associated with an improvement in sense of well-being and the recovery of libido and potency in the men who reported normal or near-normal sexual function before the start of therapy. In 7 patients with Stage D2 disease, the cancer progressed to an androgen-independent state. The mean and median times to progression were 128 weeks and 108 weeks, respectively. Seven patients have died, 1 from a noncancer-related illness, with mean and median overall survival times of 210 weeks and 166 weeks, respectively. CONCLUSIONS: Prostate cancer is amenable to control by intermittent androgen suppression. This approach affords an improved quality of life when the patient is off therapy. It also results in reduced toxicity and cost of treatment and possibly delays tumor progression. Whether survival is affected in a beneficial or adverse way remains to be studied in a randomized, prospective study.
PURPOSE: We correlated multichannel pressure-flow urodynamics and the American Urological Association (AUA) symptom index in the evaluation of benign prostatic hyperplasia. MATERIALS AND METHODS: We evaluated 121 consecutive, symptomatic patients older than 55 years with the AUA symptom score and multichannel pressure-flow urodynamic studies. Testing was performed during a single session and the data obtained from 103 patients were plotted on the Schäfer nomogram for assessment of outflow obstruction. Linear regression statistical analysis was used to determine correlations. RESULTS: There was no significant correlation between uroflowmetry and Schäfer curves (r = 0.173 to 0.326), uroflowmetry and AUA symptom scores (r = 0.134 to 0.153) and, most importantly, AUA symptom scores and Schäfer curves (r = 0.025 to 0.137). CONCLUSIONS: We conclude that these modalities measure independent variables, and should not be linked in the evaluation and treatment decision of the patient with prostatism.
We describe two patients with a T3bN2M0 renal cell carcinoma with caval extension to the hepatic veins in which we successfully utilized extracorporeal femoralaxillary venovenous bypass for tumor thrombus resection. The inherent advantage of this modified venovenous bypass are discussed with a current review of the literature.
Androgen suppression is the routine approach to the treatment of advanced prostate cancer. Using intermittent androgen suppression by taking the advantage of the reversible action of medical castration results in the maintenance of apoptotic potential. The experiments in the androgen-dependent androgen-dependent Shionogi carcinoma tumor model as well as clinical experience in a group of men with prostate malignancy are presented in this report. These consecutive cycles of androgen withdrawal and replacement afford an improved quality of life when the patient is off therapy. It is possible to reduce toxicity, cost of treatment and to delay tumor progression. Whether survival is affected in a beneficial or adverse way still remains to be studied.
Progression of an androgen-dependent tumour to an androgen-independent state is characterized by the loss of apoptotic potential, a property of cells which have differentiated under the influence of androgens. In an attempt to relate progression to mechanisms of apoptotic failure, we compared the relative levels of expression of androgen receptor and TRPM-2 (clusterin) genes in androgen-dependent and -independent tumours derived from the Shionogi carcinoma. The amount of 10 kb androgen receptor mRNA in androgen-dependent and -independent cells was similar thus showing no relationship to progression. Owing to cross-hybridization of androgen receptor cDNA with non-receptor transcripts, two new androgen-repressed mRNAs (ADS31 and ADS39) were cloned. Each was found to have a 20/21 bp GC-rich region of sequence homology with the androgen receptor, implying selective conservation of a domain whose function is unknown. Sequencing results also revealed that ADS31 cDNA encodes a polypeptide identical to mouse YPT1, a ras-related GTP-binding protein. Expression of the ADS31/YPT1, ADS39 and TRPM-2 genes was sensitive to androgen withdrawal and replacement both in the parent androgen-dependent and the recurrent androgen-independent carcinomas. The uncoupling of TRPM-2 expression and apoptosis observed in androgen-independent tumour cells implies that the function of androgen receptor becomes more restricted with tumour progression. Furthermore, the fact that the expression of ADS31/YPT1 transcript becomes dominant in the advanced stages of androgen-independent growth, suggests that the mechanism of progression is subserved by duplication and possibly redundancy of alternative (signal transduction) pathways mediating tumour cell survival and growth.
This study was undertaken to confirm the utility of systematic transrectal ultrasound-guided prostate biopsy in diagnosing cancer in patients with abnormal findings on digital rectal examination or abnormal levels of prostate-specific antigen (or both). The authors also wanted to determine the diagnostic advantage of taking six sextant biopsy samples rather than four quadrant samples. In a prospective study of 669 men examined between July 1992 and April 1993 at a tertiary-care hospital, core samples were obtained from any visualized or palpated abnormalities, the three other "normal" quadrants (apices and bases) and the two parasagittal midzones. The glands of 403 of the patients (60%) had an abnormality detectable by ultrasonography, and 233 of the patients (35%) had adenocarcinoma, proven by histologic examination. Of the 169 cases of adenocarcinoma initially indicated by ultrasonography, the suspected lesion was histologically benign in 66 (39%), but malignancy was found in another portion of the gland. In 18 (8%) of the 233 patients with adenocarcinoma, the only positive result was obtained from the additional core biopsy samples from the midzone. This study confirms that the ultrasonographic characteristics of cancer are variable, that many tumours (130 [56%] in this study) are detected in areas that are normal on ultrasonography and digital rectal examination, and that the detection sensitivity is increased (by 8% in this study) when two midlobe parasagittal plane biopsy samples are added to the four standard quadrant samples.
BACKGROUND: In response to the first administration of a luteinizing hormone-releasing hormone (LHRH) agonist, the secretion of pituitary gonadotropin increases sharply and gives rise to a transient surge in the concentration of serum testosterone. This effect reaches a peak 4 to 7 days after the start of therapy and results in the onset of clinical symptoms and signs of tumor flare in 5% to 10% of patients. METHODS: To determine whether the effects of the LHRH-induced flare reaction are preventable, cyproterone acetate (100 mg) and low-dose diethylstilbestrol (0.1 mg) were administered daily for 4 weeks to inhibit the pituitary before the initiation of therapy with a depot LHRH agonist, goserelin acetate (3.6 mg every 4 weeks). Diethylstilbestrol was stopped after 8 weeks to eliminate associated minor toxicity while administration of cyproterone acetate was continued to suppress vasomotor symptoms. Twenty-four men with histologically confirmed prostate cancer were enrolled in the study: 6 with Stage C, 2 with Stage D1, and 16 with Stage D2 disease. RESULTS: Lead-in therapy reduced the concentration of serum testosterone into the castrate range within 1 week, and no significant change was observed in the mean level after administration of goserelin acetate. Neither was there an effect on the initial rate of normalization of serum prostate specific antigen (PSA); normal PSA values were obtained in 50% of patients after 10 weeks and in 70% after 32 weeks. In the subgroup of patients with Stage D2 disease, longer median survival was predicted by a normal serum PSA, either stable or decreasing, after 32 weeks of treatment. The regimen was well tolerated with a low incidence of hot flushes. CONCLUSIONS: These results imply that in the absence of LHRH-induced tumor flare, prognosis is related to the ability of therapy to maintain a PSA nadir in the normal range.
BACKGROUND: Since postcastration progression of tumors to an androgen-independent state appears to be linked to the cessation of androgen-induced differentiation of tumorigenic stem cells, the authors hypothesized that the replacement of androgens at the end of a period of apoptotic regression might result in the regeneration of differentiated tumor cells with further apoptotic potential. METHODS AND RESULTS: To determine the effect of intermittent exposure of androgens on the androgen-dependent Shionogi carcinoma, the tumor was transplanted into a succession of male mice, each of which was castrated when the estimated tumor weight became about 3 g. After the tumor had regressed to 30% of the original weight, it was transplanted into the next noncastrated male. This cycle of transplantation and castration-induced apoptosis was repeated successfully four times before growth became androgen-independent during the fifth cycle. In four of Stage C and three of Stage D patients with prostate cancer, androgen withdrawal was initiated with cyproterone acetate (100 mg/d) and diethylstilbestrol (0.1 mg/d) and then maintained with cyproterone acetate in combination with the luteinizing hormone-releasing hormone agonist, goserelin acetate (3.6 mg/month). After 6 or more months of suppression of serum prostate-specific antigen (PSA) into the normal range, treatment was interrupted for 2 to 11 months. After recovery of testicular function, androgen-withdrawal therapy was resumed when serum PSA increased to a level of about 20 micrograms/l. This cycle was repeated sequentially to a total of two to four times over treatment periods of 21 to 47 months with no loss of androgen dependence. CONCLUSIONS: These results demonstrate that intermittent androgen suppression can be used to induce multiple apoptotic regressions of a tumor; they also suggest that the cyclic effects of such treatment on prostate cancer can be followed by the sequential measurement of serum PSA levels.
PURPOSE: To ascertain the usefulness of real-time ultrasound (US)-guided fine-needle aspiration biopsy as an adjunct to clinical, mammographic, and sonographic assessment of solid breast lesions. MATERIALS AND METHODS: US-guided fine-needle aspiration biopsy was performed in 225 malignant and 580 benign solid breast lesions confirmed by means of excisional biopsy or with imaging follow-up (mammography or US) performed at approximate intervals of 6, 12, 24, and 36 months. All lesions were classified as palpable or nonpalpable at clinical examination and visible or nonvisible on mammograms. RESULTS: In 213 malignant lesions (95%), the cytologic findings were malignant or suspicious, with no false-positive and 12 false-negative cases. Mammography did not enable detection of 58 cancers (26%), 43 of which were palpable. Fifteen cancers discovered with US were nonpalpable and not seen on mammograms. Cytologic diagnosis of fibroadenoma or nonspecific benign cells was correct in 535 lesions. The sensitivity of this method was 95%; specificity, 92%; and overall accuracy, 93%. CONCLUSION: Real-time US-guided fine-needle aspiration biopsy is a useful adjunct to clinical, mammographic, and sonographic assessment of solid breast lesions.
A polyclonal rabbit antibody to lactoferrin was used to localize the distribution of lactoferrin within the different zones of the normal human prostate as well as within the inflamed human prostate. Cases of normal central zone, peripheral zone, periurethral glandular tissue, as well as cases in which foci of moderate to severe inflammation, along with varying degrees of inflammation-related atrophy, were studied. In cases with inflammation, the staining pattern of lactoferrin was compared to the staining pattern of prostate-specific antigen. Within the central zone, lactoferrin staining occurred in numerous individual cells peppered throughout the epithelium as well as within multiple intraepithelial lumens (lacunae). These lacunae were often numerous enough to give the central zone epithelium a fenestrated appearance; they were not seen in any of the other regions of the prostate. With the exception of an occasional individual cell or isolated positive gland, normal peripheral zone exhibited very little lactoferrin activity. Staining within the transition zone was similar to that seen in the peripheral zone. Staining within the urethral lining of the epithelium in the periurethral glands showed a distinct pattern of frequent intense staining involving the entire gland; frequent individual positive cells were also often seen. Three patterns of staining were identified in prostatic inflammation. Mild periglandular chronic inflammation produced foci of epithelial lactoferrin positivity that coincided precisely with the areas of inflammation. Severe acute inflammation produced strong staining within luminal secretions while cytoplasmic staining was limited to the luminal surface of the epithelium. Post-inflammatory atrophy showed intense diffuse lactoferrin staining in the scant cytoplasm of the atrophic epithelium. In 12 of the 17 cases of inflammation that were studied, areas of post-inflammatory atrophy or severe inflammation commonly showed absence of prostate specific antigen staining and epithelium that was strongly lactoferrin-positive. Within the normal human prostate, lactoferrin appears to be produced primarily within the epithelium of the central zone, periurethral glands, and lining epithelium of the prostatic urethra. Lactoferrin-filled central zone lacunae appear to be structures unique to the central zone. The distribution of lactoferrin in the periurethral glands and urethral lining epithelium, along with the intense production of lactoferrin in the presence of inflammation, and the preservation of lactoferrin production in severe inflammation or atrophy suggest that lactoferrin may be a key component of the inflammatory response within the human prostate.
It is possible that the advent of more aggressive surgical approaches to carcinoma of the prostate, including neoadjuvant and adjuvant therapy, will lead to a higher incidence of pelvic recurrence rates in coming years. A method of sequentially monitoring the region of the urethrovesical anastomosis for early recurrence that is more accurate than digital rectal examination is required. Transrectal ultrasound is an established technique for the preoperative assessment of prostate cancer. It has also been used postoperatively to guide a biopsy needle into palpably suspicious areas at the urethrovesical junction or for random biopsies in patients with elevated prostate specific antigen levels. However, the sonographic anatomy of the postoperative urethrovesical junction has not previously been described. In this prospective study we analyze the transrectal sonographic characteristics of the neoanatomy in 30 patients, all within 3 months following surgery for clinically intracapsular disease. We describe features of the neoanatomy, such as anterior tissue nodules and anastomotic rings. Because of distinct variations in the neoanatomy of different patients we recommend early postoperative transrectal biplanar sonography to establish a baseline image for each individual case. This would be useful for later comparison and may prevent a false positive scan on subsequent followup studies.
Transrectal ultrasound may establish the diagnosis of prostatic abscess in an ambiguous clinical setting. Transurethral resection (deroofing) is the treatment preferred by many clinicians, yet intraoperative complete abscess obliteration may be difficult to confirm endoscopically. We report on a patient with a complex prostatic abscess endoscopically resected under transrectal ultrasound guidance. Adequacy of treatment was proved pathologically.
We describe a method of differentiating physiological from pathological dilatation of the renal collecting system in pregnant patients. In physiological hydronephrosis the dilated ureter extends down only to the level of the common iliac artery. In 2 patients with distal ureteral stones a dilated ureter was visualized past the vessels. To determine the frequency and reliability of visualizing the ureters in pregnant patients 105 consecutive asymptomatic pregnant patients were examined. Hydronephrosis was found in 83 kidneys in 59 of the patients. The dilated ureter was visualized in 64 of the renal units. The anatomy was well demonstrated by color flow Doppler scanning and in all of these cases the dilated ureter was seen to taper where it crossed the common iliac artery. These results suggest that the presence of a dilated ureter past the iliac artery is strong evidence for pathological distal ureteral obstruction in pregnancy.
Cyproterone acetate is a progestational antiandrogen with potent antigonadotropic activity that results in rapid suppression of serum testosterone. Used as a single agent, cyproterone acetate yields a total androgen blockade. It may be combined with low-dose diethylstilbestrol, orchiectomy, or LHRH agonists to improve, in theory, the results of such therapy. In clinical testing, cyproterone acetate has proved equivalent to diethylstilbestrol with markedly less toxicity. It is useful in conjunction with LHRH agonists, either transiently to block the flare phenomenon, or continuously to block peripheral androgen receptors; the necessity for this latter action has not yet been proved. Cyproterone acetate may afford transient objective improvement in patients not responding to other forms of hormone deprivation. Experience in this role is limited. The drug may be used to suppress the hot flushes associated with orchiectomy or LHRH agonist therapy. Cyproterone acetate induces local tumor regression; owing to its reversible effects, it is useful as neoadjuvant or adjuvant androgen withdrawal therapy in patients with lower-stage disease undergoing radical surgery or radiotherapy. Adverse effects are mostly those related to hormone withdrawal, namely, impotence, infertility, and lassitude. Gynecomastia and breast tenderness occur in less than 18% and cardiovascular complications in approximately 10% of treated men.
The parent Shionogi mouse mammary carcinoma is androgen dependent but cells that survive hormone withdrawal progress and give rise to an androgen-independent tumor. To determine whether renewed growth might be attributed to the persistence or partial recovery of an androgenic stimulus, we compared the amount of dihydrotestosterone and nuclear androgen receptor in parent and recurrent tumors. The whole tissue concentration of dihydrotestosterone in the parent tumor before castration was 1.40 +/- 0.46 (SE) as compared with 0.22 +/- 0.10 pmol/mg of DNA in the recurrent tumor. The initial concentration of nuclear androgen receptor in the parent was 0.65 +/- 0.12 pmol/mg of DNA; this was reduced to zero within 24 h after castration. Also in keeping with the androgen independence, no receptor was detected in the nuclear fraction of the recurrent carcinoma. In an attempt to relate malignant potential to nonhormonal factors associated with progression, we compared the proportions of androgen-dependent and -independent tumorigenic (stem) cells in parent and recurrent tumors using an in vivo limiting dilution assay. The difference observed, i.e., one stem cell per 4000 tumor cells in the parent versus one stem cell per 200 tumor cells in the recurrent carcinoma, was consistent with a marked enrichment of stem cells in the latter. The proportion of androgen-independent stem cells was also determined by assaying tumor takes in female hosts. The difference, i.e., one stem cell per 370,000 tumor cells in the parent versus one stem cell per 800 tumor cells in the recurrent carcinoma, demonstrated a striking 500-fold increase in androgen-independent stem cells resulting from androgen withdrawal. Unexpectedly, no enrichment of androgen-independent stem cells was evident in regressing parent tumors; rather, the proportion of such cells was very small, i.e., one androgen-independent stem cell per 2,200,000 regressing parent cells. This finding implies that the androgen-independent state of cells which survive androgen withdrawal may result from the ability of a small number of initially androgen-dependent stem cells to adapt to an altered hormone environment.
Coaxial balloon dilation catheters recently have been introduced for transurethral dilation of the prostate. We applied endoscopically a specially designed high pressure, large diameter balloon catheter to patients with benign prostatic hyperplasia or primary bladder neck hyperplasia who presented with symptomatic, cystoscopic and urodynamic evidence of obstruction. We report our preliminary experience with 42 patients: 28 with benign prostatic hyperplasia and 14 with bladder neck hyperplasia. Six months after dilation 46% of the patients demonstrated at least a 25% improvement in subjective (symptom score) and objective (corrected peak flow rate) parameters, while 6 (21%) experienced excellent (greater than 50%) symptomatic improvement despite unchanged corrected peak flow rates and 3 (11%) showed significant (greater than 50%) improvement in corrected flow rate alone. At 1, 3, 6 and 12 months the symptom scores decreased by 70, 67, 61 and 59% (median) from pre-treatment levels. Men with benign prostatic hyperplasia fared better than those with primary bladder neck hyperplasia (74 versus 58% decrease at 6 months). Objective evaluation by corrected peak flow rates demonstrated 25, 24, 28 and 2% median improvement at 1, 3, 6 and 12 months, respectively. Patients with primary bladder neck hyperplasia had substantially greater increases than those with benign prostatic hyperplasia (47 versus 27% at 6 months). Immediately after dilation the serum prostate specific antigen level increased by at least 1.5 ng. per ml. in 16 of 22 patients, indicating significant tissue trauma. Complications included mild bleeding and pain for the initial 24 hours and transient urinary retention in 2 patients. Our experience demonstrates the safety of an endoscopic approach to balloon dilation of the prostate that allows the urologist to maintain a central role in the assessment of a new approach to the treatment of obstructed voiding dysfunction.
We present our results of 3 biopsy techniques applied to each of 62 patients with clinically suspicious prostatic nodules. Transrectal digitally guided and sonographically guided transperineal fine needle aspiration biopsies were followed by digitally guided transperineal core biopsy in all cases. Adenocarcinoma was confirmed in 25 patients by 1 or more of these techniques. Our results indicated that 7 of 25 cancer cases (28 per cent) were detected by only 1 of 3 applied methods of biopsy and 56 per cent were detected by all 3 techniques. When a clinical suspicion of malignancy remains after a negative aspiration or core biopsy consideration should be given to alternative forms of biopsy to establish a diagnosis.