The role of brachytherapy in the 21st century for prostate cancer.

Men presenting with clinically confined prostate cancer have a variety of established treatment options, among them brachytherapy is gaining increased acceptance, even in the absence of randomized comparative data between brachytherapy, surgery and external radiotherapy. This review summarizes the results of low dose rate transrectal-guided transperineal permanent seed implantation brachytherapy. We present the evolution of the different treatment planning techniques and a comprehensive review of published mature data on 10-year or longer of biochemical and survival outcome for brachytherapy alone, and brachytherapy combined with supplemental external beam radiation therapy with emphasis on its impact on quality of life.

Hypoxia-inducible factor (HIF) in human tumorigenesis.

Hypoxia is a major event that occurs in most solid tumors. Intratumoral hypoxia is sufficient to activate the key transcription factor, hypoxia-inducible factor (HIF) that mediates the activation of the "survival machinery" in cancer cells. HIF can also be induced by oxygen-independent genetic alterations that activate a variety of oncogenic signaling pathways or inactivate tumor suppressors. Increased tumor HIF occurs at early stages of carcinogenesis and is often correlated with increased angiogenesis, malignant progression, poor patient prognosis and chemoradio-resistance. HIF-alpha subunit, the oxygen-regulated subunit of HIF is overexpressed in a wide range of human solid tumors. Nuclear HIF-alpha protein immunostaining was restricted to tumor cells compared to normal tissues. Herein, we review and discuss the role of HIF in tumorigenesis and describe the overexpression of HIF-alpha proteins in human cancers and its association with overall clinical outcomes.

Are consecutive nightly recordings required for valid evaluation of sleep-associated erections?

We questioned the need for more than one RigiScan recording for accurate assessment of sleep-associated penile erections and determine the necessity of consecutive nightly recordings for valid evaluation of sleep-associated erections. Men complaining of erectile dysfunction (ED) and referred to RigiScan evaluation for the first time participated. Recordings were performed at the patient's home during two consecutive nights, and data on test time, number of erections, erection duration, minimal and maximal base and tip tumescence and rigidity were retrieved for both nights. Normal erectile function was defined with the recording of at least one erection (70 out of 100% tip rigidity lasting for at least 10 min during either night). The main outcome measures were RigiScan recordings. Group 1 consisted of 29 men (mean age 42.4+/-13.8 years, range 22-71) who had normal erections, all during the first night. Group 2 consisted of 26 men (mean age 48.6+/-13.5 years, range 25-70) who failed to fulfill both criteria for normal erection. In Group 2, only the values for penile base rigidity and erection duration were normal during the first night: the parameters of maximal base tumescence, tip rigidity, number of effective erections and duration of effective erections that were impaired during the first night were significantly worse (P<0.01) during the second night. The required information for the diagnosis of psychogenic ED was obtained during the first night in >50% of the participants. Men with normal erections during the first night can be spared the inconvenience and cost of re-testing. Consecutive night recording should be reserved for patients whose recorded data during the first night did not fulfill the criteria for normal erection.

Combination therapy-permanent interstitial brachytherapy and external beam radiotherapy for patients with localized prostate cancer.

BACKGROUND: Combination of permanent interstitial brachytherapy based on radioactive iodine with external beam radiotherapy is an alternative to other treatment modalities, such as radical prostatectomy or external beam radiotherapy alone in patients with intermediate-risk localized prostate cancer. In this article we report our experience with this combination modality. METHODS: Among patients who were treated in our institute with brachytherapy, there were 64 patients who received combination therapy for the above indication. Combination therapy enables administration of 110 Gy as brachytherapy and thereafter 45 Gy as external beam radiation. All patients received adjuvant androgen deprivation therapy for 6 months. The prospective follow-up was done with the aid of validated evaluation instruments (questionnaires). RESULTS: Combination therapy was administered without additional urinary (IPSS-based) or sexual (IIEF-based) side effects above those with brachytherapy alone. No severe perianal and lower intestinal tract side effects were observed. Short-to-moderate-term results based on serum PSA levels are encouraging, and are not inferior to what is accepted by the literature for other radical therapies. CONCLUSION: Combination of permanent interstitial brachytherapy and external beam radiotherapy in the appropriate patients does not cause any additional morbidity, and its biochemical results justify its application. This modality should be offered as an accepted and good alternative to other radical treatment options, to men with prostate cancer with moderate risk factors.

Per urethra insertion of a through-and-through safety guide wire using a dual-lumen ureteral catheter during percutaneous nephrolithotripsy.

BACKGROUND: The second ("safety") of two guide wires is commonly inserted antegradely in percutaneous nephrolithotripsy (PCNL). We describe the retrograde insertion of a through-and-through safety guide wire during PCNL. METHODS: After inserting a percutaneous nephrostomy 1 day earlier, a guide wire was introduced through the nephrostomy tube to the bladder and pulled out through the urethral meatus via a cystoscope and grasper. The tube was removed, leaving the wire positioned from the flank to the meatus. A dual-lumen catheter was introduced retrogradely through the urethra over the wire, up to the nephrostomy incision. The safety guide wire was introduced retrogradely through the catheter's other port. RESULTS: This procedure succeeded in 9 of 10 patients: the exception was very obese and the catheter was too short to reach the incision in the flank. CONCLUSION: Using a dual-lumen catheter allows quick and simple retrograde insertion of a safety guide wire during PCNL.

Gene therapy of prostate cancer: current and future directions.

Prostate cancer (PCA) is the second most common cause of death from malignancy in American men. Developing new approaches for gene therapy for PCA is critical as there is no effective treatment for patients in the advanced stages of this disease. Current PCA gene therapy research strategies include cytoreductive approaches (immunotherapy and cytolytic/pro-apoptotic) and corrective approaches (replacing deleted or mutated genes). The prostate is ideal for gene therapy. It is an accessory organ, offers unique antigens (prostate-specific antigen, prostate-specific membrane antigen, human glandular kallikrein 2 etc.) and is stereotactically accessible for in situ treatments. Viral and non-viral means are being used to transfer the genetic material into tumor cells. The number of clinical trials utilizing gene therapy methods for PCA is increasing. We review the multiple issues involved in developing effective gene therapy strategies for human PCA and early clinical results.

Sildenafil versus the vacuum erection device: patient preference.

PURPOSE: We evaluated the preference of patients with erectile dysfunction who had been effectively treated with a vacuum erection device and then switched to sildenafil. MATERIALS AND METHODS: A total of 52 patients with erectile dysfunction who achieved satisfactory erectile function according to the International Index of Erectile Function (IIEF) while using a vacuum erection device were switched to an increasing dose of sildenafil (range 25 to 100 mg.) until satisfactory erection was maintained at least twice a week for at least 1 month. The 2 treatment methods were not used concomitantly. A total of 36 patients with a mean age of 59 years (range 35 to 77) who claimed to have achieved satisfactory erections with a vacuum erection device and sildenafil reported their preference to continue sildenafil or resume the use of a vacuum erection device, reasons for the choice and any adverse side effects. RESULTS: Of the 36 participants in whom the efficacy of sildenafil was similar to that of a vacuum erection device according to the IIEF scores (mean plus or minus standard deviation 61.6 +/- 10.4 and 62.5 +/- 6, respectively), 12 (33.3%) decided to resume use of a vacuum erection device (group 1) while 24 (66.6%) preferred to continue sildenafil (group 2). There were no statistically significant differences between the groups regarding patient age or the etiology and duration of erectile dysfunction. The increase in the IIEF score while using a vacuum erection device was higher in group 1 than 2, with a mean of 66.75 versus 60.4, respectively (p = 0.002). The adverse side effects of sildenafil were the main reasons for preferring a vacuum erection device. Fewer ejaculatory difficulties, efficacy, comfort and ease of use were the main reasons for choosing sildenafil. CONCLUSIONS: Even in an era of effective oral medication, the vacuum erection device remains a preferred treatment option for a substantial number of patients with erectile dysfunction.

Dialysis access induced limb ischemia corrected using quantitative duplex ultrasound.

Dialysis access induced limb ischemia (DAILI) is a rare complication after the creation of an arteriovenous fistula in infancy but can cause irreversible ischemic limb damage in severe cases. The incidence of DAILI is higher in bridge graft fistulas than in native fistulas. DAILI patients may be managed by surgically reducing the volume flow in the fistula. However, in the pediatric age group, such a reduction of volume flow may result in thrombosis or an inadequate flow for effective dialysis. Several methods have been described to achieve the delicate balance between essential flow in the fistula and adequate limb perfusion pressure. We have developed a new method employing preoperative duplex ultrasonography to predict quantitatively the reduction in volume flow in the fistula that will allow effective dialysis while providing adequate limb perfusion. The preoperative assessment was reproduced on the operating table using intraoperative duplex. A 3-year-old girl thus treated has had resolution of her ischemic symptoms and maintains long-term patency of her dialysis access.

Clinical efficacy of sildenafil in patients on chronic dialysis.

PURPOSE: We evaluate the clinical efficacy of sildenafil citrate for patients who are on chronic dialysis and who have concomitant erectile dysfunction. MATERIALS AND METHODS: A total of 35 men (mean age 60.7 years) on dialysis and with erectile dysfunction of various etiologies were administered 25 to 100 mg sildenafil for at least 6 months. The International Index of Erectile Function questionnaire (IIEF), a global assessment question and partner satisfaction question were used to evaluate sildenafil efficacy. Patients also reported any adverse events that occurred during treatment. RESULTS: Treatment was effective for 28 of the 35 (80%) patients according to the results of the IIEF and global assessment questions. Partner satisfaction correlated with the IIEF overall response (0.79) and global assessment question results (0.86). No correlation was found between sildenafil failure and patient age, the etiology of erectile dysfunction, duration of erectile dysfunction, prior treatments, testosterone and prolactin blood levels, and the duration and etiology of renal failure. Of the 35 patients sildenafil was stopped due to intolerable headaches in 3 and because of lack of efficacy in 7. CONCLUSIONS: Sildenafil is an effective and safe treatment for erectile dysfunction in most patients on chronic dialysis.

Decision-making in pediatric varicocele surgery: use of color Doppler ultrasound.

Although varicoceles are common in adolescence, the indications for surgery as well as the procedure of choice are controversial. We have evaluated the use of color Doppler ultrasound (CDUS) as an objective tool in the assessment of such patients in a 5-year prospective study for determination of varicocele size, venous flow patterns, testicular volume, and resistance index. A high ligation was performed only when reverse blood flow was demonstrable in the varicocele during a Valsalva maneuver, and a low approach when this finding was absent. Twenty-six boys underwent low ligation and 53 high ligation based on the findings of CDUS. The incidence of recurrence (3.8%) was lower than that encountered by the same surgical team prior to introduction of CDUS (20.5%) (P = 0.004). These results are even more striking when contrasted with published recurrence rates of 12% to 15% (P = 0.015 to 0.003). Thus, CDUS proved to be a useful tool in selecting the proper surgical approach for varicocele in adolescence. The incidence of recurrence was significantly reduced following the introduction of this procedure.

Management of dialysis access-associated steal syndrome: use of intraoperative duplex ultrasound scanning for optimal flow reduction.

Dialysis access-associated steal syndrome (DASS) is an uncommon complication after the creation of an arteriovenous fistula and can cause irreversible ischemic damage in severe cases. Dialysis access-associated steal syndrome has been managed with the surgical reduction of the volume flow in the fistula, but this is associated with a certain incidence of access loss. Several methods are described to achieve the delicate balance between essential flow in the fistula and an adequate limb perfusion pressure. We have developed a new method with duplex ultrasound scanning to quantitate the reduction in volume flow, which will allow effective dialysis and provide adequate limb perfusion. The preoperative assessment was reproduced on the operating table with intraoperative duplex scanning. A 65-year-old woman who underwent this treatment has had resolution of her ischemic symptoms and maintains long-term patency of her dialysis access.

The substrates of a sodium- and chloride-coupled gamma-aminobutyric acid transporter protect multiple sites throughout the protein against proteolytic cleavage.

Fragments of the (Na(+) + Cl-)-coupled GABAA transporter were produced by proteolysis of membrane vesicles and reconstituted preparations from rat brain. The former were digested with Pronase, the latter with trypsin. Fragments with different apparent molecular masses were recognized by sequence-directed antibodies raised against this transporter. When GABA was present in the digestion medium, the generation of these fragments was almost entirely blocked. At the same time, the neurotransmitter largely prevented the loss of activity caused by the protease. The effect was specific for GABA; protection was not afforded by other neurotransmitters. It was only observed when the two cosubstrates, sodium and chloride, were present on the same side of the membrane as GABA. The results indicate that the transporter may exist in two conformations. In the absence of one or more of the substrates, multiple sites located throughout the transporter are accessible to the proteases. In the presence of all three substrates--conditions favoring the formation of the translocation complex--the conformation is changed such that these sites become inaccessible to protease action.

Neuronal and glial gamma-aminobutyric acid+ transporters are distinct proteins.

In the central nervous system, two subtypes of sodium- and chloride-coupled GABA transporter exist. One is sensitive to ACHC, the other to beta-alanine. They are thought to be of neuronal and glial origin, respectively. GABA transport in membrane vesicles derived from astroglial cells was found to be sodium- and chloride-dependent, electrogenic and much more sensitive to beta-alanine than to ACHC. Immunoblotting with antibodies directed against a variety of sequences of the ACHC-sensitive transporter indicated that none of these epitopes was shared by the glial transporter.

Neither amino nor carboxyl termini are required for function of the sodium- and chloride-coupled gamma-aminobutyric acid transporter from rat brain.

Antibodies were raised against synthetic peptides corresponding to several regions of the rat brain gamma-aminobutyric acid (GABA) transporter. According to our model, this glycoprotein has 12 transmembrane alpha-helices with both amino and carboxyl termini located in the cytoplasm. The antibodies recognized the intact transporter on Western blots. Upon papain treatment, a reconstitutively active transporter can be isolated upon lectin chromatography (Kanner, B. I., Keynan, S., and Radian, R. (1989) Biochemistry 28, 3722-3728). The papainized transporter runs on sodium dodecyl sulfate-polyacrylamide gels as a broad band with an apparent molecular mass between about 58 and 68 kDa as compared to 80 kDa for the untreated transporter. The transporter fragment was recognized by all the antibodies, except for that raised against the amino terminus. Pronase cleaves the transporter to a relatively sharp 60-kDa band, which reacts with the antibodies against the internal loops but not with either the amino- or the carboxyl-terminal. This pronase-treated transporter, upon isolation by lectin chromatography, was reconstituted. It exhibits full GABA transport activity. This activity exhibits the same features as the intact system including an absolute dependence on sodium and chloride as well as electrogenicity. We conclude that the amino- and carboxyl-terminal parts of the transporter, possibly including transmembrane alpha-helices 1, 2, and 12, are not required for the transport function.

Low-affinity gamma-aminobutyric acid transport in rat brain.

The low-affinity (Km = 100-200 microM) gamma-aminobutyric acid (GABA) transporter from membrane vesicles from rat brain has been characterized and found to be in many aspects similar to the well-known sodium- and chloride-coupled high-affinity gamma-aminobutyric acid transporter (Km = 2-4 microM). Influx by this system is sodium and chloride dependent and stimulated by an interior negative membrane potential. Steady-state levels obtained by both systems are lowered by the sodium channel openers veratridine and aconitine. However, while the channel blocker tetrodotoxin fully reverses this inhibition with the high-affinity system, this is not the case for its low-affinity counterpart. Furthermore, the toxin from the scorpion Androctonus australis Hector inhibited high-affinity transport only. Efflux of gamma-aminobutyric acid taken up by the high-affinity system displayed a Km of about 100 microM. Exchange catalyzed by the low-affinity system was observed in the absence of external sodium and chloride. Furthermore, both activities copurified in the fractionation procedure developed to purify the high-affinity transporter. All these observations are consistent with the idea that both activities are manifestations of only one gamma-aminobutyric acid transporter. The high-affinity binding site represents the extracellular and the low-affinity site the cytosolic aspect of the transporter. In addition, it was found that right-side-out synaptosomes also contain a low-affinity GABA transporter. This apparently represents a different transport protein.