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M Garzotto

Publications and source records attributed to M Garzotto.

At least 19 recordsLinked to original sources
PubMed2004

Multiple cycles of intermittent chemotherapy in metastatic androgen-independent prostate cancer.

Recently, completed phase III studies demonstrated a survival benefit for a fixed number of cycles of docetaxel-containing chemotherapy treatment of androgen-independent prostate cancer (AIPC). Management of patients who respond well to initial chemotherapy for AIPC remains ill-defined. We previously reported that in a select group of such patients, retreatment with the same regimen was feasible and was associated with quality of life gains. Here, we report that multiple cycles of such intermittent chemotherapy are feasible. We prospectively tested intermittent chemotherapy in eight AIPC patients responding to calcitriol plus docetaxel who reached a serum prostate-specific antigen (PSA) <4 ng ml(-1) (22% of the 37 patients who were initially treated with this regimen). Chemotherapy was suspended until a rise in PSA > or =50% and 1 ng ml(-1). The median duration of the first treatment holiday was 20 weeks (13-74 weeks) and all patients retained sensitivity to retreatment. Four patients were eligible for a second chemotherapy holiday, and the median duration was 21 weeks (17-28 weeks). Two patients elected to take a third chemotherapy holiday, which lasted 10 and 28 weeks. The median time to treatment failure was 26.5 months (95% CI 23.6-29.4 months), and the median survival is 41 months (95% CI 33.7-48.3 months). Multiple cycles of intermittent chemotherapy interrupted by clinically meaningful treatment holidays are feasible in a subset of AIPC patients treated with this docetaxel-containing regimen. Intermittent chemotherapy for AIPC is feasible and deserves further study.

Aged↗
PubMed2004

Imatinib mesylate and zoledronic acid in androgen-independent prostate cancer.

OBJECTIVES: To determine the safety and efficacy of zoledronic acid (Zometa) combined with imatinib mesylate (Gleevec) in patients with bone pain due to androgen-independent prostate cancer. METHODS: Fifteen patients were treated with zoledronic acid 4 mg intravenously every 28 days and imatinib mesylate 400 mg/day. The pain response, defined as a 2-point reduction in the Present Pain Intensity Scale or normalization if the initial score was 1, was the primary endpoint. Secondary endpoints included palliative response, prostate-specific antigen response, measurable disease response, time to progression, impact on quality of life, decrease in markers of bone turnover, and tolerability of the drug combination. RESULTS: The study was stopped early because of a lack of activity. No palliative or clinical activity was detected for the combination, and no prostate-specific antigen responses were observed. The median time to progression was 4 weeks (95% confidence interval 3 to 5), and the median duration of treatment was 8 weeks (range 1.6 to 16.7). The median overall survival was 54 weeks (95% confidence interval 18 to 90). Therapy was associated with a reduction in urine N-telopeptides and a trend toward a reduction in serum osteocalcin, but no change occurred in bone-specific alkaline phosphatase. CONCLUSIONS: In this patient population, imatinib mesylate and zoledronic acid produced no prostate-specific antigen responses and had no palliative or clinical activity.

Aged↗
PubMed2004

Delayed therapy with curative intent in a contemporary prostate cancer watchful-waiting cohort.

OBJECTIVE: To identify predictors of delayed therapy with curative intent, an increasingly common option in contemporary patients with prostate cancer who initially choose watchful waiting. PATIENTS AND METHODS: The characteristics of all patients at one institution and diagnosed with T1-4NXM0 prostate cancer between 1993 and 2000 were prospectively recorded. Factors recorded included: age, tumour stage, histological type, Gleason score, serum prostate specific antigen (PSA) level, prostate volume, PSA density (PSAD), percentage of positive biopsy cores, and the initial treatment selection. Outcomes, including all cancer-directed interventions, all serum PSA values, and initial outcomes of all interventions with curative intent, were determined by review of all medical records and cancer registry data. RESULTS: Of 187 patients on watchful waiting, 175 had stage T1 or T2 cancer and were analysed primarily. Thirty-eight (22%) of these patients received delayed intervention with curative intent (15 radical prostatectomy, 17 external beam radiotherapy, six brachytherapy). Age (P < 0.001) and percentage of positive biopsy cores (P = 0.042) were significant independent predictors of intervention with curative intent. When the PSA doubling time was added to the model it became a significant predictor (P = 0.018), with percentage positive biopsy cores (P = 0.022) and age (P < 0.001). CONCLUSIONS: Therapy with curative intent is common in contemporary patients with prostate cancer who initially choose watchful waiting. Age and percentage positive biopsy cores are independent predictors of such intervention, with PSA doubling time also an independent predictor.

Adenocarcinoma↗
PubMed2003

Intermittent chemotherapy in metastatic androgen-independent prostate cancer.

Intermittent use of chemotherapy for androgen-independent prostate cancer (AIPC) instead of treatment until disease progression may reduce toxicity. We prospectively tested this approach in eight AIPC patients responding to calcitriol plus docetaxel who reached a serum prostate-specific antigen (PSA) <4 ng ml(-1). Chemotherapy was suspended until a rise in PSA>/=50% and 1 ng ml(-1). The median duration of treatment holiday was 20 weeks (13-43+weeks) and all patients retained sensitivity to re-treatment. Chemotherapy holiday was associated with an improvement of fatigue (P=0.05). Intermittent chemotherapy for AIPC is feasible and deserves further study.

Aged↗
PubMed2001

Weekly high-dose calcitriol and docetaxel in advanced prostate cancer.

Novel treatment regimens for androgen-independent prostate cancer (AIPC) are needed because currently available approaches have not been shown to improve survival. Docetaxel provides a good foundation for new therapeutic combinations because of its promising single-agent activity against prostate cancer and its favorable tolerability profile, particularly when administered weekly. In both tissue culture and animal models of prostate cancer, calcitriol (the biologically active form of vitamin D) enhanced the activity of docetaxel, paclitaxel, and platinum compounds. These effects were particularly notable at supraphysiologic calcitriol concentrations. Weekly calcitriol dosing is associated with minimal toxicity and permits substantial dose escalation over the daily schedule. A weekly calcitriol dose of 0.5 microg/kg produces plasma calcitriol levels 25-fold higher than the physiologic range. In a preclinical study at the Oregon Health Sciences University, calcitriol 5 micromol/L plus docetaxel 0.15 nmol/L was at least additive in inhibiting PC-3 colony formation. A phase II study is evaluating weekly administration of 0.5 microg/kg calcitriol orally on day 1 followed by 36 mg/m(2) docetaxel intravenously on day 2 in patients with AIPC (repeated for 6 consecutive weeks of each 8-week cycle). At the time of a preliminary analysis, 11 patients had been enrolled and were actively being treated. All 5 patients who had completed 8 weeks of calcitriol/docetaxel treatment achieved prostate-specific antigen (PSA) reductions of > or =50%. Two of these patients had confirmatory assessments, both meeting the formal PSA response criteria. Treatment has been well tolerated, with 1 patient experiencing a self-limited grade 3 toxicity and no patients experiencing grade 4 or 5 toxicities.

Adenocarcinoma↗
PubMed2001

Tumor-suppressive effects of neutral endopeptidase in androgen-independent prostate cancer cells.

Expression of neutral endopeptidase (NEP) 24.11 is diminished in metastatic, androgen-independent prostate cancers (PCs; C. N. Papandreou et al., NAT: MED:, 4: 50--57, 1998). To determine the effects on androgen-independent PC cells of overexpressing cell-surface NEP, an inducible tetracycline-regulatory gene expression system was used to stably introduce and express the NEP gene in androgen-independent TSU-Pr1 cells generating WT-5 cells, which expressed high levels of enzymatically active NEP protein when cultured in the absence of tetracycline. TN12 cells, which contain the identical vectors without the NEP gene and do not express NEP, were used as control. Expression of NEP in WT-5 cells after removal of tetracycline from the media resulted in a >80% inhibition in cell proliferation over a 1-week period (P < 0.005) compared with control cells. Tumor formation occurred in the prostate glands of orthotopically injected athymic mice killed at 30 days in 4 of 5 mice that were given injections of 2 x 10(6) WT-5 cells and were fed doxycycline (NEP suppressed), and in all mice that were given injections of TN12 cells and were fed with or without doxycycline. In contrast, only 1 of 5 mouse prostates developed a tumor in mice that were given injections of WT-5 cells and that did not receive doxycycline. Analysis of the mechanisms of NEP-induced growth suppression revealed that NEP expression in WT-5 cells induced a 4-fold increase in the number of PC cells undergoing apoptosis, and increased the expression of p21 tumor suppressor gene protein and the level of unphosphorylated retinoblastoma protein as determined by Western blot. Flow cytometric analysis show that induced NEP expression in WT-5 cells resulted in a G(1) cell cycle arrest. These data show that NEP can inhibit PC cell growth and tumorigenicity and suggest that NEP has potential as therapy for androgen-independent PC.

Androgens↗
PubMed2001

Current concepts in risk factor assessment for advanced germ cell cancer.

Disseminated germ cell tumors (GCT) have come to represent the model for a curable malignancy, as cure rates with cisplatin-based chemotherapy coupled with appropriate surgery are 70% to 80%. For patients with favorable prognostic factors who achieve and maintain a complete response, the outlook is good. However, despite advances in the treatment of this disease, a significant number of patients with metastatic GCT fail to respond either primarily or secondarily. Being able to identify poor-risk patients up front would allow for appropriate selection of candidates for high-risk trials. Several different classification systems were previously developed at several treatment centers in the United States and Europe. These models recognized different clinical variables as prognosticators and had unique functional properties. However, these served as precursors to the International Germ Cell Consensus Classification that was developed to establish a universally accepted standard. The development of this system has allowed for valid comparisons of ongoing and future trials. Furthermore, this system will serve to encourage international collaboration for the study of high-risk GCT.

Antineoplastic Agents↗
PubMed2000

Historical perspective on prostate brachytherapy.

Brachytherapy--radiation delivered close to or within a tumor--had its origins at the beginning of this century. Its use in prostate cancer was delayed first by the view that this was a relatively radioresistant cancer and then by clinical experience showing high failure and morbidity rates. More recently, technological innovations such as ultrasonography and computer-based treatment planning have made prostate brachytherapy a reasonable treatment option for many patients.

Brachytherapy↗
PubMed2000

Combined androgen deprivation with radiotherapy for prostate cancer: does it make sense?

Currently, our understanding of the mechanism(s) of radiation-induced death of prostate cancer is limited. In-depth analysis of these processes would facilitate the design of more effective treatment strategies utilizing radiation therapy. An increasingly recognized form of radiation-induced death is postmitotic apoptosis. In this process, radiation damages the tumor cell s DNA. The cell then divides prior to completing DNA repair, an event that is lethal. In order to avoid this fate, the cancer cell may attempt to halt its cell-cycle machinery temporarily to repair its DNA prior to dividing. In the treatment of prostate cancer, radiation therapy currently is being evaluated in combination with androgen deprivation (AD). However, because AD can induce growth arrest, it may reduce the effectiveness of radiation through a reduction in postmitotic apoptosis. To study this effect, we examined the effect of AD on prostate cancer radiosensitivity as it is related to cell-cycle progression. Androgen-sensitive prostate cancer cells demonstrated increased resistance to radiation when deprived of androgenic stimuli. Thus, paradoxically, AD may reduce the radiosensitivity of prostate cancer by means of cell-cycle delay, which results in a reduction in postmitotic apoptosis.

Androgens↗
PubMed1999

Reversal of radiation resistance in LNCaP cells by targeting apoptosis through ceramide synthase.

Cell lines derived from human prostate cancer are regarded as relatively resistant to both radiation-induced clonogenic death and apoptosis. Here we attempted to modulate the response of LNCaP prostate cancer cells to radiation therapy (XRT) by pretreatment with 12-O-tetradecanoylphorbol acetate (TPA), a known apoptogenic agent in LNCaP cells. Using plateau-phase cultures, we investigated the response of these cells to XRT, TPA, and a combination of XRT and TPA. LNCaP irradiation did not result in ceramide generation or apoptosis. However, pretreatment with TPA enabled XRT to generate ceramide via activation of the enzyme ceramide synthase and signal apoptosis. Apoptosis was abrogated by the competitive inhibitor of ceramide synthase, fumonisin B1. Furthermore, when transplanted orthotopically into the prostate of nude mice, LNCaP cells produced tumors that recapitulated the responses of LNCaP cells in vitro. XRT or TPA failed to signal apoptosis in LNCaP tumors, whereas a combination of the two resulted in substantial (20-25%) apoptosis within 24 h. There was an additional benefit associated with this regimen because TPA pretreatment protected the adjacent rectum from radiation-induced apoptosis. This represents the first description of signaling-based therapy designed to overcome one form of radiation resistance expressed preferentially in LNCaP human prostate cancer cells.

Animals↗
PubMed1998

12-O-tetradecanoylphorbol-13-acetate-induced apoptosis in LNCaP cells is mediated through ceramide synthase.

Protein kinase C (PKC) activation is often antiapoptotic, although in a few cell types PKC initiates apoptosis by an unknown mechanism. Recent investigations showed that activation of PKC alpha by 12-O-tetradecanoylphorbol 13-acetate (TPA) induced apoptosis in LNCaP prostate cancer cells. The present studies examine the mechanism of this effect and show that de novo ceramide generation through the enzyme ceramide synthase is required. TPA induced rapid ceramide generation, which was detectable by 1 h and increased linearly for 12 h. TPA-induced apoptosis was measurable by 12 h and was progressive for 48 h. Investigations into the mechanism of TPA-induced ceramide generation revealed that acid and neutral sphingomyelinase activities were not enhanced. However, TPA induced an increase in ceramide synthase activity that persisted for at least 16 h. Treatment with fumonisin B1, a specific natural inhibitor of ceramide synthase, abrogated both ceramide production and TPA-induced apoptosis. Ceramide analogues bypassed fumonisin B1 inhibition to initiate apoptosis directly. Thus, ceramide appears to be a necessary signal for TPA-induced apoptosis in LNCaP cells. This represents the first description of a pathway by which PKC may signal apoptosis.

Amidohydrolases↗
PubMed1998

Androgen deprivation with salvage surgery for radiorecurrent prostate cancer: results at 5-year followup.

PURPOSE: We studied the effect of the combination of androgen deprivation with salvage surgery in patients with radiorecurrent prostate cancer. MATERIALS AND METHODS: Salvage cystoprostatectomy or radical prostatectomy was performed in 29 patients with radiorecurrent prostate cancer. Of the 29 patients 24 had been treated with neoadjuvant hormonal therapy before salvage surgery, while in 5 an initial trial of androgen deprivation had failed preoperatively. RESULTS: The positive surgical margin rate for all patients was 31%. Margin involvement correlated strongly with disease specific and disease-free survival. At a mean followup of 5.3 years disease specific survival was 95% in men with negative surgical margins compared with 44% in those with positive surgical margins (p = 0.002). Similarly, clinical and biochemical disease-free survival was 80% in patients with negative surgical margins, while only 44% of those with positive surgical margins remained disease-free (p = 0.05). Surgical margins were positive in 80% of the men in the androgen deprivation failure group and in 21% in the neoadjuvant hormonal therapy group (p = 0.001). The disease specific survival rate after an initial trial of androgen deprivation failed was only 20% compared with 92% after neoadjuvant hormonal therapy was given preoperatively (p = 0.001) CONCLUSIONS: The combination of neoadjuvant hormonal therapy with salvage surgery for radiorecurrent prostate cancer resulted in a low incidence of surgical margin involvement, which correlated strongly with disease specific and disease-free survival. Patients with radiorecurrent prostate cancer in whom an initial trial of androgen deprivation fails appear to be poor candidates for salvage prostatectomy.

Antineoplastic Agents, Hormonal↗
PubMed1997

Lipopolysaccharide induces disseminated endothelial apoptosis requiring ceramide generation.

The endotoxic shock syndrome is characterized by systemic inflammation, multiple organ damage, circulatory collapse and death. Systemic release of tumor necrosis factor (TNF)-alpha and other cytokines purportedly mediates this process. However, the primary tissue target remains unidentified. The present studies provide evidence that endotoxic shock results from disseminated endothelial apoptosis. Injection of lipopolysaccharide (LPS), and its putative effector TNF-alpha, into C57BL/6 mice induced apoptosis in endothelium of intestine, lung, fat and thymus after 6 h, preceding nonendothelial tissue damage. LPS or TNF-alpha injection was followed within 1 h by tissue generation of the pro-apoptotic lipid ceramide. TNF-binding protein, which protects against LPS-induced death, blocked LPS-induced ceramide generation and endothelial apoptosis, suggesting systemic TNF is required for both responses. Acid sphingomyelinase knockout mice displayed a normal increase in serum TNF-alpha in response to LPS, yet were protected against endothelial apoptosis and animal death, defining a role for ceramide in mediating the endotoxic response. Furthermore, intravenous injection of basic fibroblast growth factor, which acts as an intravascular survival factor for endothelial cells, blocked LPS-induced ceramide elevation, endothelial apoptosis and animal death, but did not affect LPS-induced elevation of serum TNF-alpha. These investigations demonstrate that LPS induces a disseminated form of endothelial apoptosis, mediated sequentially by TNF and ceramide generation, and suggest that this cascade is mandatory for evolution of the endotoxic syndrome.

Adipose Tissue↗
PubMed1997

Prostate cancer.

Explore the source record for details and available documents.

Humans↗
PubMed1996

Factors affecting size and configuration of electrovaporization lesions in the prostate.

OBJECTIVES: Transurethral electrovaporization of the prostate is a new, minimally invasive technique being used by urologists for surgical ablation of prostatic tissue. There are insufficient data concerning factors affecting the vaporization and coagulation lesions produced by this technique. The aim of this study was to determine the role of various parameters for adequate tissue evaporation. METHODS: This study compared bovine liver and human prostatic lesions made by the Vaportrode instrument with those produced by standard electrocautery loops, roller balls, and laser fibers. Additionally, two electrosurgical instruments with differing technical capabilities were compared for their ability to cause vaporization of tissue. RESULTS: Results revealed that the Vaportrode lesions were maximal with a new electrode when used with a Force 40S electrosurgical generator set at 300 W and a drag speed of 25 to 30 seconds per 10 mm of tissue. The lesions produced by this technique had a 74% greater coagulation volume compared to a standard cautery loop. The evaporation defect was comparable to a laser lesion produced in contact at 60 W. CONCLUSIONS: We conclude that electrovaporization under optimal conditions causes a vaporization lesion comparable to that produced by high power density laser prostatectomy. Additionally, the coagulation volume of a vaportrode lesion is considerably greater than that produced by standard electrocautery resection.

Animals↗
PubMed1996

Transurethral vaportrode electrovaporization of the prostate: physical principles, technique, and results.

OBJECTIVES: This is a study to evaluate technique, efficacy, and safety of a new electrosurgical instrument (Vaportrode) in management of benign prostatic hyperplasia (BPH). METHODS: Forty-two symptomatic BPH patients form the subject of this study. Preoperative and postoperative International Prostate Symptom Score (IPSS), peak flow rates (PFR), postvoid residual urine (PVR), operative details, and complications were recorded in each patient. Baseline, 1, 3, and 6 months follow-up data were used for analyses. RESULTS: Results reveal that transurethral electrovaporization of the prostate (TUEVP) is a reasonable procedure to treat symptomatic BPH, and at 6 months, this procedure results in 68% reduction in IPSS, 128% improvement in PFR, and 58% reduction in PVR. Even in patients who are in retention prior to TUEVP, at 6 months the IPSS is 7.7, PFR is 20.4 cc/s, and PVR reduces to 130 cc. The procedure is well tolerated without any significant short-term complications. CONCLUSIONS: The results of this modality in improving the symptoms and PFR in symptomatic BPH patients in the short term appear promising. Advantages over transurethral resection (TUR) of the prostate and laser prostatectomy include familiarity of the transurethral route, lack of need for high-cost laser equipment and fibers, excellent intraoperative hemostasis, lack of bleeding or fluid absorption, and ability to cause a predictable TUR-like prostate defect at the end of the procedure. Further studies involving larger numbers of patients and longer follow-up are warranted to assess further the utility of this procedure.

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