Combined androgen blockade therapy can convert RT-PCR detection of prostate-specific antigen (PSA) and prostate-specific membrane antigen (PSMA) transcripts from positive to negative in the peripheral blood of patients with clinically localized prostate cancer and increase biochemical failure-free survival after curative therapy.

BACKGROUND: The clinical relevance of positive molecular staging as defined by reverse transcriptase-polymerase chain reaction (RT-PCR) detections of both prostate-specific antigen (PSA) and prostate-specific membrane antigen (PSMA) transcripts in the peripheral blood (PB) of patients with prostate cancer is still debatable. METHODS: We analyzed the biochemical failure-free survival (bFFS) of prostate cancer patients with positive molecular staging who underwent immediate curative therapy (Group I, n=39) compared to prostate cancer patients who did convert their positive molecular staging by the administration of combined androgen blockade (CAB) for 12 months prior to curative treatment (Group II, n=15). RESULTS: The median bFFS for Group I was 9 months (95% CI 5-13 months) and was significantly lower compared to Group II (>36 months, p<0.001). In Group I, the median time for PSA values of >2.0 ng/mL was 18 months (95% CI 12-21 months, range 12-36 months). Notably, only one patient from Group II reached PSA values>2.0 ng/mL at 36 months post-curative treatment. CONCLUSIONS: In patients with clinically localized prostate cancer and positive RT-PCR detection of PSA and PSMA transcripts in PB, CAB can convert positive molecular staging status to negative and by doing so it modifies the post-curative therapy bFFS of patients with clinically localized prostate cancer.

Randomized controlled clinical trial of a combination of somatostatin analog and dexamethasone plus zoledronate vs. zoledronate in patients with androgen ablation-refractory prostate cancer.

BACKGROUND: As previously shown, the combination of standard androgen ablation therapy with somatostatin analog and dexamethasone in metastatic androgen ablation-refractory (stage D3) prostate cancer (PrCa) patients has a favorable profile of side-effects, durable objective antitumor activity (up to 60% partial response rate) and palliative effects. Bisphosphonates interfere with bone remodeling at the sites of PrCa bone metastases and have been postulated to have indirect and/or direct anti-PrCa activity. MATERIALS AND METHODS: A randomized controlled clinical trial was conducted to compare a combination of somatostatin analog (octreotide 20 mg i.m. every 28 days) and oral dexamethasone (4 mg daily for 1 month, gradually reduced to 1 mg daily by the fourth month, with a 1 mg daily maintenance dose thereafter) plus zoledronate (4 mg i.v. every 4 weeks) vs. zoledronate only. All patients in both arms remained in basic androgen blockade throughout the study. RESULTS: Thirty-eight stage D3 patients (mean age 72.8 +/- 6.8 years) were randomized to either treatment arm of the study. The trial was stopped after a pre-specified interim analysis met the criteria for early closure, i.e. significant difference in outcomes between the two treatment arms. Partial responses (PR, > or =50% PSA decline) were observed in 13 out of 20 patients with combination therapy vs. none with zoledronate. The combination therapy arm had significantly better outcome with respect to median progression-free survival (7.0 vs. 1.0 months, p < 0.0001), median overall survival (OS) (12.0 vs. 9.0 months, p = 0.0027), median PrCa-specific OS (defined as time from onset of therapy until PrCa-related death) (16 vs. 9.0 months, p = 0.0005) and median duration of bone pain improvement (>14 vs. 4 months p = 0.00001 by log-rank tests). CONCLUSION: For androgen ablation-refractory metastatic PrCa patients under androgen ablation, the combination of dexamethasone, somatostatin analog and zoledronate offered superior objective and palliative clinical responses than zoledronate alone.

Serum testosterone: A potentially adjunct screening test for the assessment of the risk of prostate cancer among men with modestly elevated PSA values (> or =3.0 and <10.0 ng/ml).

Whether serum testosterone (T) can become an adjunct test able to validate the PSA-weighted risk of prostate cancer (PR.CA) in the "grey" diagnostic area (PSA =3.0 to <10.0 ng/ml) was investigated. Seven hundred and eighteen men participated in a prostate screening program using the cutoff PSA value of > or =3.0 ng/ml. PR.CA was found in 26% (22/85) of men with PSA testing within the "grey" diagnostic area and 58% (7/12) with PSA testing > or =10 ng/ml, among the 97 men who agreed to undergo transrectal ultrasound-guided biopsy (TRUS-guided biopsy). The PSA values showed a statistically significant positive association with diagnosis of PR.CA, whereas T and the T/PSA ratio were inversely and significantly related to the disease. In addition, out of 718 subjects, 45 (2.6%) were found to have a T value <2.6 ng/ml and another 78 (10.8%) had "low normal T value" (2.6> or = T <3.0 ng/ml). Of the hypogonadal men, 16 received testosterone enanthate (depot T; 250 mg/ml oily injection, intramuscularly: i.m.; TRT) and three had PSA levels >3.0 ng/mlpost-TRT; one was eventually diagnosed with PR.CA. An empirically-determined cut-off of the T/PSA ratio [>95 ("negative") or <0.95 ("positive")] was found to be optimal with regard to both sensitivity/specificity. This test was "positive" among 95.5% of the PR.CA patients, whereas 81% of biopsies confirmed that non-PR.CA had a "negative" TIPSA ratio, indicating that this ratio can become an adjunct screening test in assessing the risk of PR. CA; in particular, the odds of PR. CA increasing sharply (1/0.08= 12.5 times) with a decrease of the TIPSA ratio by one standard deviation. We conclude that the measurement of the serum T value can become an adjunct test validating further the PSA-weighted risk of PR. CA within the "grey" diagnostic area.

Combination therapy using LHRH and somatostatin analogues plus dexamethasone in androgen ablation refractory prostate cancer patients with bone involvement: a bench to bedside approach.

The development of resistance to anticancer therapies is a major hurdle in preventing long-lasting clinical responses to conventional therapies in hormone-refractory prostate cancer. Herein, the molecular evidence documenting that bone metastasis microenvironment survival factors (mainly the paracrine growth hormone-independent, urokinase-type plasminogen activator-mediated increase of IGF-1 and the endocrine production of growth hormone-dependent IGF-1, mainly liver-derived IGF-1 production) produce an epigenetic form of prostate cancer cells that are resistant to proapoptotic therapies is reviewed. Consequently, the authors present the conceptual framework of a novel antibone microenvironment survival factor, mainly an anti-IGF-1 hormonal manipulation for androgen ablation refractory prostate cancer (a combination of conventional androgen ablation therapy [luteinising hormone-releasing hormone agonist-A or orchiectomy]) with dexamethasone plus somatostatin analogue, which yielded durable objective responses and major improvement of bone pain and performance status in stage D3 prostate cancer patients.

Morbidity of prophylactic inguinal lymphadenectomy with saphenous vein preservation for squamous cell penile carcinoma.

BACKGROUND: Inguinal lymphadenectomy has an essential role in the cure of patients with inguinal metastasis from penile cancer; however, this procedure is associated with a significant morbidity. In recent years, modified lymphadenectomy with saphenous vein preservation has been postulated to reduce morbidity. Herein, we present our recent experience with prophylactic inguinal lymhadenectomy and saphenous vein preservation in patients with invasive penile carcinoma and non-palpable inguinal lymph nodes. METHODS: Seven patients with invasive squamous cell penile carcinoma, who underwent bilateral prophylactic inguinal lymphadenectomy with saphenous vein preservation between 1995 and 2001, were reviewed retrospectively. Mean age was 67.7 years. The pathological stage of the primary tumor was pT2 in four and pT3 in three patients respectively. Postoperative complications were defined as minor--wound infection, seroma formation requiring drainage, and skin necrosis, and major-- deep venous thrombosis, persistent seroma formation, flap necrosis requiring a skin graft, as well as permanent and disabling leg lymphedema. RESULTS: Minimum follow up was 2 years. Minor complications--wound infection--occurred in one patient (one groin). No major complications occurred. All patients are alive without evidence of disease recurrence. CONCLUSIONS: Prophylactic inguinal lymphadenectomy seems to offer reduced morbidity in high risk penile cancer patients without compromising survival outcome.

The large bladder diverticulum in children.

OBJECTIVE: Large bladder diverticulae, i.e. with a diameter measuring at least one-third of the bladder diameter on voiding cystourethrography, constitute an unusual but serious cause of obstructive uropathy in childhood. Their operative management entails meticulous reconstruction of the lower urinary tract. We report our experience with the management and long-term outcome of large bladder diverticulae in children during a 20-year period. PATIENTS AND METHODS: Twenty-two children (21 boys and 1 girl) aged 13 days to 14 years old (median age 2 years) at diagnosis of a large bladder diverticulum were treated in our department between April 1982 and December 2001. Presenting symptoms were: acute pyelonephritis in 10 patients, acute or chronic urinary retention in five, recurrent non-febrile bacteriuria in four and macroscopic hematuria in one patient. In the remaining two cases the diverticulae were diagnosed incidentally. Vesicoureteral reflux due to incorporation of the ureter within the diverticulum occurred in three children (four ureters). Transvesical diverticulectomy was performed as primary treatment in 20 patients. In the remaining two who presented at the age of 2 weeks with acute retention, cutaneous vesicostomy was the primary management followed after 1 year by diverticulectomy. Diverticulectomy was combined with ureteral reimplantation in 14 ureters (four refluxing and 10 non-refluxing) which were incorporated within the diverticular sac. In two children with bladder-neck hypertrophy, a bladder neck incision was additionally performed. RESULTS: There were two postoperative complications. In one case of bladder-neck stenosis with a thick trabeculated bladder ureterovesical obstruction occurred following ureteral reimplantation. Another patient presented with severe hematuria and clot retention, which was controlled by clot evacuation, continuous bladder irrigation and administration of factor VIII. In the five patients with retention preoperatively, complete bladder emptying was achieved postoperatively. Seventeen patients who at their last follow up had reached school age had a normal uroflow and normal voiding patterns. None of the patients had recurrence of the diverticulum, and all have remained free of urinary infection postoperatively during a mean (range) follow-up period of 16 (2-20) years. CONCLUSION: Large bladder diverticulae present a serious urological problem in childhood. Urinary infection and urinary retention are the most common presenting symptoms. Transvesical diverticulectomy is a reliable technique for surgical treatment, and can effectively be combined with ureteral reimplantation or with the management of associated bladder-neck pathology whenever necessary. In neonates a staged approach with primary cutaneous vesicostomy followed by diverticulectomy is recommended as a safer but equally effective treatment.

Combination of somatostatin analog, dexamethasone, and standard androgen ablation therapy in stage D3 prostate cancer patients with bone metastases.

PURPOSE: Androgen ablation-refractory prostate cancer patients (stage D3) develop painful bone metastases and limited responsiveness to conventional therapies, hence the lack of universally accepted "gold standard" treatment for this poor prognosis clinical setting. We tested the safety and efficacy in stage D3 patients of the combination hormonal therapy, which combines administration of somatostatin analog and dexamethasone with standard androgen ablation monotherapy (luteinizing-hormone releasing-hormone analog or orchiectomy). EXPERIMENTAL DESIGN: Thirty eight patients with stage D3 prostate cancer (mean age 71.8 +/- 5.9 years) continued receiving androgen ablation therapy in combination with oral dexamethasone (4 mg daily for the 1st month of treatment, tapered down to 1 mg daily by the 4th month, with 1 mg daily maintenance dose thereafter) and somatostatin analog (20 mg octreotide i.m. injections every 28 days). RESULTS: Twenty-three of 38 patients (60.5%) receiving this combination regimen had partial responses [PR, >/=50% prostate-specific antigen (PSA) decline], 9 (21.1%) had stable disease, and 7 (18.4%) had progressive disease. In 47.7% (18 of 38) of patients, their serum PSA levels decreased with treatment but did not return to their respective baselines until the end of follow-up (or death from non-prostate cancer-related causes). The median time-to-return to baseline PSA was 12 months (95% CI, 7-17 months), median progression-free survival was 7 months (95% CI, 4.5-9.5 months), median overall survival was 14 months (95% CI, 10.7-17.4 months), and median prostate cancer-specific overall survival (defined as time from onset of combination therapy until prostate cancer-related death) was 16.0 months (95% CI, 11.9-20.1 months). All patients reported significant and durable improvement of bone pain and performance status (for a median duration of 14 months; 95% CI, 9-19 months), without major treatment-related side effects. We observed a statistically significant (P < 0.01) reduction in serum insulin-like growth factor-1 levels at response to the combination therapy. T levels remained suppressed within castration levels at baseline and throughout therapy, including relapse. CONCLUSION: The combination therapy of dexamethasone plus somatostatin analog and standard androgen ablation manipulation produces objective clinical responses and symptomatic improvement in androgen ablation-refractory refractory prostate cancer patients.

Syndrome of inappropriate antidiuretic hormone secretion in a patient with hormone refractory prostate cancer.

The syndrome of inappropriate antidiuretic hormone secretion (SIADH) may occur in a variety of diseases, including malignancies, and can be induced by drugs. We report a case of inappropriate antidiuretic hormone syndrome associated with hormone refractory prostatic carcinoma.

Combined androgen blockade-induced anemia in prostate cancer patients without bone involvement.

BACKGROUND: To determine the onset and extent of combined androgen blockade (CAB)-induced anemia in prostate cancer patients without bone involvement. PATIENTS AND METHODS: Forty-two patients with biopsy-proven prostatic adenocarcinoma [26 with stage C (T3N0M0) and 16 with stage D1 (T3N1M0)] were included in this study. All patients received CAB [leuprolide acetate (LHRH-A) 3.75 mg, intramuscularly, every 28 days plus 250 mg flutamide, tid, per Os] and were evaluated for anemia by physical examination and laboratory tests at baseline and 4 subsequent intervals (1, 2, 3 and 6 months post-CAB). Hb, PSA and Testosterone measurements were recorded. Patients with stage D2-3 disease, abnormal hemoglobin level or renal and liver function tests that were higher than the upper limits were excluded from the study. The duration of the study was six months. RESULTS: The mean hemoglobin (Hb) levels were significantly declined in all patients from baseline of 14.2 g/dl to 14.0 g/dl, 13.5 g/dl, 13.2 g/dl and 12.7 g/dl at 1, 2, 3 and 6 months post-CAB, respectively. Severe and clinically evident anemia of Hb < 11 g/dl with clinical symptoms was detected in 6 patients (14.3%). This CAB-induced anemia was normochromic and normocytic. At six months post-CAB, patients with severe anemia had a Hb mean value of 10.2 +/- 0.1 g/dl (X +/- SE), whereas the other patients had mild anemia with Hb mean value of 13.2 +/- 0.17 (X +/- SE). The development of severe anemia at 6 months post-CAB was predictable by the reduction of Hb baseline value of more than 2.5 g/dl after 3 months of CAB (p = 0.01). The development of severe CAB-induced anemia in prostate cancer patients did not correlate with T baseline values (T < 3 ng/ml versus T > or = 3 ng/ml), with age (< 76 yrs versus > or = 76 yrs), and clinical stage (stage C versus stage D1). Severe and clinically evident anemia was easily corrected by subcutaneous injections (3 times/week for 1 month) of recombinant erythropoietin (rHuEPO-beta). CONCLUSION: Our data suggest that rHuEPO-beta correctable CAB-induced anemia occurs in 14.3% of prostate cancer patients after 6 months of therapy.

Combination of dexamethasone and a somatostatin analogue in the treatment of advanced prostate cancer.

The local microenvironment at the sites of cancer metastases protects tumour cells from anticancer drug-induced apoptosis via mechanisms, such as soluble growth factors and cytokines. The concept of antisurvival factor (ASF) therapy as a component of anticancer treatments aims at neutralising the protective effect conferred upon cancer cells by the survival factor(s) derived by the local microenvironment, in order to enhance the sensitivity and/or reverse the resistance of tumour cells to other anticancer therapeutic strategies. Herein, we review the translation of this concept from ex vivo studies to clinical applications in the setting of prostate cancer refractory to androgen ablation (stage D3). At this stage, which predominantly involves bone metastases, insulin-like growth factor 1 (IGF-1) production (either growth hormone (GH)-dependent or GH-independent) can protect tumour cells from apoptosis, despite the significant suppression of androgens. The application of the ASF therapeutic concept involves the combination of dexamethasone (which suppresses GH-independent IGF-1) and somatostatin analogue (which suppresses endocrine, GH-dependent IGF-1) with the pro-apoptotic effect of the testicular androgen suppression by sustained use of LHRH analogues. In stage D3, patients who had failed anti-androgen withdrawal, chemotherapy and also had several other adverse prognostic features, the ASF-based combination achieved durable objective responses and major symptomatic improvement, paving the way for future applications of this approach. The ASF-based combination therapy illustrates a novel paradigm in cancer treatment: anti-tumour treatment strategies may not only aim at directly inducing cancer cell apoptosis, but can also target the tumour microenvironment and neutralise the protection it confers on metastatic cancer cells. The favourable toxicity profile of this therapeutic approach calls for its testing in a randomised controlled setting in metastatic prostate cancer and, conceivably, in other IGF-1-responsive malignancies.

Molecular evidence-based use of bone resorption-targeted therapy in prostate cancer patients at high risk for bone involvement.

BACKGROUND: To improve median survival of patients with prostate cancer that has metastasized to bone, we need to better understand the early events of the metastatic process in skeleton and develop molecular tools capable of detecting the early tumor cell dissemination into bones (micrometastasis stage). However, the initial phase of tumor cell dissemination into the bone marrow is promptly followed by the migration of tumor cells into bone matrix, which is a crucial step that signals the transformation of micrometastasis to macrometastasis stage and clinically evident metastasis. The migration of cancer cells into bone matrix requires the activation of local bone resorption. Such an event contributes to tumor cell hiding/ escaping from high immunologic surveillance of bone marrow cells. Within bone matrix, tumor cells are establishing plethoric cell-cell interactions with bone marrow-residing cells, ensuring their survival and growth. Recently, RT-PCR detections of tumor marker transcripts, such as PSA and PSMA mRNA performed in RNA extracts of peripheral blood nucleated cells and bone marrow biopsy, have enabled the stratification of patients with clinically localized prostate cancer being of high risk for extraprostatic disease and bone involvement. Therefore, it is conceivable that bisphosphonate blockade of bone resorption can inhibit the migration of tumor cells into bone matrix during the early phase of disease dissemination into bone marrow (micrometastasis stage). Consequently, assessment of the efficacy and efficiency of bisphosphonates to arrest the evolution of bone lesions in this particular clinical setting of patients with clinically localized prostate cancer and positive molecular staging status (high risk for bone involvement) is warranted.