Docetaxel and epirubicin compared with docetaxel and prednisone in advanced castrate-resistant prostate cancer: a randomised phase II study.

BACKGROUND: This randomised phase II study compared the activity and safety of the combination docetaxel (D)/epirubicin (EPI) with the conventional treatment D/prednisone (P) in advanced castrate-resistant prostate cancer (CRPC) patients. MATERIALS AND METHODS: Patients were randomly assigned to D 30 mg m(-2) as intravenous infusion (i.v.) and EPI 30 mg m(-2) i.v. every week (D/EPI arm), or D 70 mg m(-2) i.v. every 3 weeks and oral P 5 mg twice daily (D/P arm). Chemotherapy was administered until disease progression or unacceptable toxicity. RESULTS: A total of 72 patients were enrolled in the study and randomly assigned to treatment: 37 to D/EPI and 35 to D/P. The median progression-free survival (PFS) was 11.1 months (95% CI 9.2-12.6 months) in the D/EPI arm and 7.7 months (95% CI 5.7-9.4 months) in the D/P arm (P=0.0002). The median survival was 27.3 months (95% CI 22.1-30.8 months) in the D/EPI arm and 19.8 months (95% CI 14.4-24.8 months) in the D/P arm (P=0.003). Both regimens were generally well tolerated. CONCLUSION: The treatment of advanced CRPC with weekly D combined with weekly EPI was feasible and tolerable, and led to superior PFS than the treatment with 3-weekly D and oral P.

Rechallenge of docetaxel combined with epirubicin given on a weekly schedule in advanced castration-resistant prostate cancer patients previously exposed to docetaxel and abiraterone acetate: a single-institution experience.

The aim of this paper was to evaluate the activity and tolerability of weekly docetaxel (D) combined with weekly epirubicin (EPI) in patients with advanced castrate-resistant prostate cancer (CRPC) previously exposed to D and abiraterone acetate (AA). Locally advanced or metastatic CRPC patients with 0-2 performance status, who had progressed after D and AA therapy, were included in the study. Previous treatment with chemotherapy agent cabazitaxel was also admitted. Treatment consisted of D 30 mg/m(2) intravenously (i.v.) and EPI 30 mg/m(2) i.v., every week (D/EPI). Chemotherapy was administered until disease progression or unacceptable toxicity. In our institution, twenty-six patients received D/EPI: their median age was 72 years (range 59-83 years). Twenty-three (88.5%) patients had bone metastases. A decrease in PSA levels ≥50% was observed in seven patients (26.9%, 95% CI: 0.11-0.47); of these, five had achieved a ≥50% PSA response during prior first-line D and six had achieved a PSA response during prior AA Among the subjects who were symptomatic at baseline, pain was reduced in nine patients (38.1%) with a significant decrease in analgesic use. Median progression-free survival was 4.4 months (95% CI, 3-5.2), and median overall survival was 10.7 months (95% CI, 8.9-18.4). Treatment was well tolerated and no grade 4 toxicities were observed. Our findings suggest that weekly D/EPI is feasible and active in heavily pretreated advanced CRPC patients and seem to support the hypothesis that the addition of EPI to D may lead to overcome the resistance to D in a subgroup of patients.

Motor response of the human isolated colon to capsaicin and its relationship to release of vasoactive intestinal polypeptide.

The aim of this study was to obtain indirect evidence of the presence of capsaicin-sensitive afferents in the human colon by studying the motor response to capsaicin of longitudinal strips from the human isolated taenia coli in parallel to the ability of capsaicin or KCl to induce peptide release from the human superfused colon. Capsaicin (1 microM) evoked a relaxation of the taenia, approaching 60-80% of the response to isoprenaline. Tachykinins evoked contractions of the taenia, while calcitonin gene-related peptide induced a relaxation. Neither tachyphylaxis to calcitonin gene-related peptide nor preincubation with an anti-calcitonin gene-related peptide serum did block the response to capsaicin which was also unaffected by tetrodotoxin, apamin, naloxone or an anti-galanin serum. Vasoactive intestinal polypeptide produced a concentration-dependent tetrodotoxin-resistant relaxation which was shifted rightward in the presence of anti-vasoactive intestinal polypeptide serum. The anti-vasoactive intestinal polypeptide serum reduced the response to capsaicin and application of capsaicin prevented the ability of anti-vasoactive intestinal polypeptide serum to block exogenous vasoactive intestinal polypeptide. Capsaicin (1 microM) evoked a significant release of vasoactive intestinal polypeptide-like immunoreactivity from the superfused muscle but not mucosa of the human colon. A significant vasoactive intestinal polypeptide-like immunoreactivity release was also observed in response to KCl (80 mM). KCl but not capsaicin evoked a significant release of neurokinin A-like immunoreactivity from colonic muscle and mucosa. No significant release of either substance P-, neuropeptide Y-, galanin- or calcitonin gene-related peptide-like immunoreactivity was detected in response to capsaicin or KCl although detectable levels of each peptide were evident in tissue extracts.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of NG-monomethyl L-arginine (L-NMMA) and NG-nitro L-arginine (L-NOARG) on non-adrenergic non-cholinergic relaxation in the circular muscle of the human ileum.

1. We have investigated the effect of the NO synthesis inhibitors, NG-monomethyl L-arginine (L-NMMA) and NG-nitro L-arginine (L-NOARG) on the non-adrenergic non-cholinergic (NANC) relaxation produced by electrical field stimulation in the circular muscle of the human ileum. 2. In the presence of atropine and guanethidine (1 and 3 microM, respectively), electrical field stimulation produced tetrodotoxin-sensitive relaxation of the strips. L-NMMA, starting from 100 microM, produced a concentration-dependent inhibition of the evoked relaxations (2Hz); maximal inhibition at 1 mM averaged about 35%. 3. The inhibitory effect of L-NMMA was unchanged by previous incubation with D-arginine while it was prevented by L-arginine (L-Arg). L-NMMA did not affect isoprenaline-induced relaxation. 4. L-NOARG (1-30 microM) concentration-dependently inhibited the evoked relaxations at 2 Hz, up to a maximum of 65% inhibition, although in some strips complete inhibition of the response was observed. The effect of L-NOARG was reversed by L-Arg. L-NOARG did not affect isoprenaline-induced relaxation. 5. These results suggest that NO may be involved in inhibitory NANC transmission in the circular muscle of the human ileum.

Multiple sources of calcium for contraction of the human urinary bladder muscle.

1. KCl, carbachol, neurokinin A and endothelin produced concentration-dependent contractions of mucosa-free muscle strips from the dome of the human urinary bladder. The maximal response to carbachol or neurokinin A exceeded that to KCl, while the maximal response to endothelin approached that to KCl. 2. Nifedipine (1 microM) abolished the response to KCl, reduced the response to carbachol or neurokinin A but had no effect on the response to endothelin. Bay K 8644 (1 microM) markedly potentiated the response to KCl but had little or no effect on the response produced by the other stimulants. 3. Superfusion of the strips with a nominally calcium (Ca)-free medium containing EDTA (1 mM) for 30 min markedly reduced the response to carbachol, neurokinin A and endothelin, although a small response was still evident at high concentrations. Likewise, after a prolonged (60 min) superfusion of the strips with a high K (80 mM) Ca-free medium plus EDTA (1 mM) these three agonists still produced a small contractile response. 4. The nifedipine (1 microM) resistant response to carbachol, neurokinin A or endothelin was markedly depressed by LaCl3 (1 mM). In contrast, the nifedipine-(1 microM) resistant response to carbachol was not modified by NiCl2 (0.1 mM) or omega-conotoxin (0.1 microM). 5. Caffeine produced divergent effects depending upon the temperature of incubation: a relaxation at 37 degrees C and a concentration-dependent (2.5-20 mM) contraction at 25 degrees C. The latter was markedly inhibited by procaine (3 mM) but unaffected by nifedipine (1 microM). 6. After a prolonged (60 min) superfusion with a high K, Ca-free medium containing EDTA the response to carbachol (100 microM) was abolished by previous exposure to procaine (3 mM). Conversely, the response to endothelin (1 microM) was unaffected by procaine. The response to endothelin in these experimental conditions was also resistant to LaCl3 (1 mM). 7. These findings indicate that multiple sources of Ca are mobilized for contraction of the human bladder muscle by different stimulants. Dihydropyridine- and voltage-sensitive Ca channels provide the major if not the sole source of Ca for the response to KCl, play some role in the response to muscarinic (carbachol) or NK-2 tachykinin receptor stimulation but are not involved in the response to endothelin. Carbachol, neurokinin A and endothelin all mobilize a Ca pool (either extracellular or located at membrane level) which is LaCl3-sensitive but nifedipine-resistant. Neither T- nor N-type channels appear to be involved in the response to carbachol. In addition, these agents mobilize a tightly bound Ca pool independently from membrane depolarization. This latter pool is probably a procaine-sensitive intracellular source of activator Ca mobilized by caffeine and carbachol. The failure of procaine to prevent the response to endothelin in high K, Ca-free medium raises the possibility that this peptide mobilizes an intracellular source of activator Ca, distinct from the caffeine- and carbachol-sensitive pool.

Motor response of the human isolated small intestine and urinary bladder to porcine neuromedin U-8.

1. Porcine neuromedin U-8 produced a concentration (0.3 nM-1 microM)-dependent contraction of the longitudinal muscle of the human isolated ileum, which was unaffected by either atropine (1 microM) or tetrodotoxin (1 microM). 2. By contrast, neuromedin U-8 had only a weak effect on the circular muscle of the human isolated ileum. 3. Neuromedin U-8 also produced a concentration-dependent contraction of mucosa-free muscle strips from the dome of the human isolated urinary bladder, its action being unaffected by either atropine or tetrodotoxin. 4. These findings indicate that neuromedin U-8 exerts a direct contractile effect on smooth muscle of the human intestinal and urinary tract.

Potent contractile activity of endothelin on the human isolated urinary bladder.

Endothelin (1 nM-0.3 microM) produced a concentration-related contraction of mucosa-free muscle strips excised from the dome of the human urinary bladder. The response to endothelin was unaffected by either atropine (1 microM) or nifedipine (1 microM) at concentrations that abolished the response to carbachol and KCl, respectively. These findings indicate that mechanisms other than activation of dihydropyridine- and voltage-sensitive calcium channels may be involved in the action of endothelin on smooth muscles.

MEN 10,573 and MEN 10,612, novel cyclic pseudopeptides which are potent tachykinin NK-2 receptor antagonists.

The activity and selectivity of MEN 10,573 and MEN 10,612, novel cyclic pseudopeptides which are selective tachykinin NK-2 receptor antagonists is described, as compared to that of previously characterized linear and cyclic compounds. For the NK-2 receptor, the activity of test compounds was investigated in the hamster isolated trachea (HT) and the endothelium-deprived rabbit isolated pulmonary artery (RPA), two preparations which are endowed with pharmacologically distinct forms of the NK-2 receptor. The novel cyclic pseudopeptides, MEN 10,573 and MEN 10,612 displayed very high affinity for the NK-2 receptor in the HT (pA2 8.66 and 9.06, respectively) which is higher than that observed in the RPA (pA2 7.31 and 7.41 for MEN 10,573 and MEN 10,612, respectively). The antagonism exerted by MEN 10,573 and MEN 10,612 was of competitive nature in both preparations. MEN 10,573 and MEN 10,612 also displayed competitive antagonism for NK-2 receptor-mediated responses in the rabbit bronchus (RB), rat vas deferens (RVD), circular muscle of the human colon (HUC) and ileum (HUI). In the RB, HUC and HUI, the potency of the novel cyclic pseudopeptides was comparable to that of MDL 29,913 and about 10-fold greater than that of L659,877. In the RVD however, the potency of MEN 10,573 MEN 10,612 or MDL 29,913 was similar to that of L659,877. In anaesthetized rats, i.v. injection of MEN 10,612 produced a selective and long-lasting blockade of the urinary bladder contraction produced by the i.v. injection of the NK-2 receptor selective agonist [beta Ala8]neurokinin A(4-10), without affecting the response to the NK-1 receptor selective agonist [Sar9]substance P sulfone.(ABSTRACT TRUNCATED AT 250 WORDS)

Caval extension of renal cell carcinoma. Results of surgical treatment.

Twenty-eight patients with renal cell carcinoma extending to the vena cava underwent surgical treatment consisting of radical nephrectomy and removal of tumor thrombus, which was at the level of the renal veins in 23 cases, the hepatic veins in 4, and extending above the diaphragm in 1 case. In 7 patients lymph nodes were invaded, and 8 had both positive nodes and extrarenal tumor diffusion discovered at surgery. The mean survival was 41.7 months for patients with only venous extension of the tumor, 16 months for patients with positive nodes, and 10.2 months for those with both nodal and extrarenal tumor diffusion.

Ruthenium red as a selective capsaicin antagonist of the motor response to capsaicin in the human isolated ileum.

We have investigated the effect of ruthenium red, omega-conotoxin fraction GVIA (CTX) and tetrodotoxin (TTX) on the relaxation produced in the circular muscle of the human isolated ileum by capsaicin, electrical field stimulation (EFS) or vasoactive intestinal polypeptide (VIP). Ruthenium red (10 microM) selectively blocked the capsaicin-evoked relaxation while leaving the response to EFS or VIP unaffected. CTX had no significant effect on the various stimuli. TTX blocked the relaxation due to EFS but not that due to capsaicin or VIP. It is concluded that capsaicin excitation of primary afferents in the human ileum, leading to VIP release and muscle relaxation, occurs with mechanisms similar to those operating in animal tissues and that ruthenium red acts as a selective capsaicin antagonist in the human ileum.

NK2 tachykinin receptors and contraction of circular muscle of the human colon: characterization of the NK2 receptor subtype.

The contractile effect of substance P, neurokinin A, receptor selective agonists for tachykinin receptors and NK2 tachykinin receptor antagonists was investigated in mucosa-free circular strips of the human isolated colon. Neurokinin A and substance P produced concentration-dependent contractions which approached 80-90% of the maximal response to carbachol. Neurokinin A was about 370 times more potent than substance P. The action of neurokinin A and substance P was not modified by peptidase inhibitors (bestatin, captopril and thiorphan, 1 microM each). The NK2 receptor selective agonist, [beta-Ala8]neurokinin A-(4-10) closely mimicked the response to neurokinin A while NK1 and NK3 receptor selective agonists were active only at microM concentrations. The pseudopeptide, MDL 28,564, which is one of the most selective NK2 ligands available, behaved as a full agonist. Responses to [beta-Ala8]neurokinin A were antagonized by NK2 receptor selective antagonists, with the rank order of potency MEN 10,376 greater than L 659,877 much greater than R 396. These data indicate that NK2 tachykinin receptors play a dominant role in determining the contraction of the circular muscle of the human colon to peptides of this family. The NK2 receptor subtype responsible for this effect belongs to the same subtype (NK2A) previously identified in the rabbit pulmonary artery and guinea-pig bronchi.

Galanin: a potent modulator of excitatory neurotransmission in the human urinary bladder.

Galanin (GAL) produced a concentration (0.3-100 nM)-related inhibition of the atropine-sensitive component of the contractions induced by field stimulation of detrusor strips from the dome of the human urinary bladder. GAL had an ED50 of 2 nM for the inhibition. The effect of GAL was prevented by atropine (1 microM) and was not seen when the strips were stimulated with a cholinomimetic or KCl. These data suggest a possible neuromodulator role of GAL in the human urinary bladder.

Contractile response of the human isolated urinary bladder to neurokinins: involvement of NK-2 receptors.

The contractile response to substance P (SP), neurokinin A (NKA) and arginin-neurokinin B (Arg-NKB) (a water soluble analogue of NKB) was investigated in detrusor muscle strips from the dome of the urinary bladder obtained from patients undergoing total cystectomy for carcinoma of the bladder base. Spontaneous activity and response to nerve stimulation indicated that the material used in this study has characteristics similar to those described for 'normal' human detrusor muscle. All neurokinins induced a concentration-related contraction with sensitivity at nM concentrations and the following rank order of potency: NKA (90) greater than Arg-NKB (22) greater than SP (1). These findings indicate the involvement of NK-2 receptors in the contractile response of human detrusor muscle to neurokinins.

Specific motor effects of capsaicin on human jejunum.

Capsaicin (1 microM) produced a biphasic effect on the motility of longitudinal muscle strips from human jejunum e.g. an initial inhibitory effect on nerve-mediated contractions followed by a delayed increase in motility. Neither effect was observed upon a second application of the drug, indicating desensitization, a proposed marker of the action of capsaicin on sensory nerves. Both substance P and neurokinin A produced a contraction of isolated human jejunum, while calcitonin gene-related peptide had a small and inconsistent inhibitory effect.

Direct evidence for the involvement of vasoactive intestinal polypeptide in the motor response of the human isolated ileum to capsaicin.

Capsaicin (1 microM) produced complex motor responses in longitudinal and circular muscle strips from the human isolated small intestine (jejunum and ileum). In the longitudinal muscle, inhibition of the nerve-mediated contractions (electrical field stimulation) was the dominant response, while capsaicin had a weak and inconsistent effect on tone and spontaneous activity. In contrast, relaxation and decreased spontaneous activity were the responses of the circular muscle to capsaicin. These effects of capsaicin were not reproduced by a second application of capsaicin, indicating desensitization, a feature of the specific action of this drug on sensory nerves. All the effects of capsaicin in the longitudinal and circular muscle were closely mimicked by exogenous vasoactive intestinal polypeptide (VIP). Further, the inhibitory motor effect of capsaicin in both muscle layers was blocked by an anti VIP serum. In the longitudinal muscle, VIP, like capsaicin, inhibited the electrically evoked nerve-mediated contractions but not the tetrodotoxin-resistant myogenic contractions, suggesting a prejunctional site of action. The inhibitory effect of both capsaicin and VIP in the circular muscle was tetrodotoxin-resistant suggesting direct inhibition of muscle cells. Capsaicin (1 microM) evoked a tetrodotoxin-resistant release of VIP-like immunoreactivity from the human small intestine. On high pressure liquid chromatography, a major peak of the immunoreactive material released by capsaicin co-eluted with authentic VIP and a minor, unidentified peak eluted shortly afterward. We conclude that authentic VIP is involved in the local motor response to capsaicin in the human small intestine. These findings raise the possibility that VIP might be present in sensory nerves of the human gut from which it is released by capsaicin.

Release of VIP- but not CGRP-like immunoreactivity by capsaicin from the human isolated small intestine.

Exposure to capsaicin (1 microM) produced a prompt and sustained release of vasoactive intestinal polypeptide-like immunoreactivity (VIP-LI) from mucosa-free strips of human small intestine (jejunum and ileum). A second application of capsaicin, 60 min later, had no effect indicating complete desensitization, a specific feature of the action of capsaicin on sensory nerves. By contrast no release of calcitonin gene-related peptide (CGRP)-LI was produced upon the first or second application of capsaicin.

Human isolated small intestine: motor responses of the longitudinal muscle to field stimulation and exogenous neuropeptides.

(1) Longitudinal muscle strips from the human small intestine (jejunum/ileum) responded to electrical field stimulation (1-50 Hz) with frequency-related primary contractions which were largely atropine- (3 microM) sensitive. When the tone was raised by addition of galanin (0.3-1 microM), prostaglandin (PG) E2 (1-10 microM) or neurokinin A (NKA, 0.1 microM), a frequency-related relaxation was evident which was potentiated by atropine. All the responses to field stimulation were abolished by tetrodotoxin (1 microM), thus indicating their neural origin. (2) The atropine-sensitive primary contraction to field stimulation was virtually abolished by omega conotoxin fraction GVIA (CTX, 0.1-0.3 microM) while the relaxations were CTX-resistant. The field stimulation-induced relaxations, which were observed in the presence of atropine and guanethidine (3 microM), were also unaffected by apamin (0.1 microM). (3) NKA and substance P (SP) produced a concentration- (1 nM-1 microM for both peptides) related contraction, NKA being about 53 times more potent than SP. [Pro9]SP sulphone and [MePhe7]-NKB, selective agonists of the NK-1 and NK-3 receptor, respectively, were barely effective. On the other hand, [beta Ala8]NKA(4-10), a selective NK-2 receptor agonist, had a potent contractile activity, similar to that of NKA. (4) Galanin (1 nM-1 microM) produced an atropine- and tetrodotoxin-resistant concentration-related contraction of longitudinal muscle of human isolated small intestine. The response to galanin did not show any sign of fading and was particularly suitable to study the evoked relaxations.(ABSTRACT TRUNCATED AT 250 WORDS)

Human isolated ileum: motor responses of the circular muscle to electrical field stimulation and exogenous neuropeptides.

(1) Circularly-oriented muscle strips from the human ileum responded to electrical field stimulation (1-50 Hz) with frequency-related primary relaxation at low frequency and primary contractions at high frequencies of stimulation. Both responses were abolished or markedly reduced by tetrodotoxin (1 microM). (2) Atropine (3 microM) or omega conotoxin (0.1 microM) reduced but dit not abolish contraction to electrical field stimulation and enhanced the relaxation. Omega conotoxin (0.1 microM) did not affect carbachol-induced contraction nor isoprenaline-induced relaxation. (3) Neurokinin A and substance P (1 nM-1 microM) produced a concentration-dependent contraction. The NK-1 receptor selective agonist, [Pro9]SP sulfone and the NK-2 receptor selective agonist [beta Ala8]NKA(4-10) produced a contraction superimposable to that of substance P and neurokinin A, respectively. On the other hand, [MePhe7]-neurokinin B, an NK-3 receptor selective agonist was ineffective up to 1 microM. The response to substance P or neurokinin A was unaffected by atropine (3 microM). (4) Galanin, up to 0.1 microM, produced a weak and inconsistent contraction. (5) Vasoactive intestinal polypeptide (10 nM-1 microM) produced a concentration-dependent relaxation while human alpha calcitonin gene-related peptide exerted a weak and inconsistent relaxant effect. (6) These findings indicate that both cholinergic excitatory and non-cholinergic inhibitory nerves affect the motility of the circular muscle of the human small intestine. Transmitter release from excitatory nerves seems largely mediated by activation of omega conotoxin-sensitive (N-type) calcium channels. Tachykinins exert a potent contractile effect, independently of cholinergic nerves, via NK-1 and NK-2 receptors.

Locked nailing in subtrochanteric fractures of the femur in the elderly patient.

Subtrochanteric fractures are a typical pathology in the elderly patient, they are not very common and they are difficult to treat. The general conditions of these patients, often at the limit of operability, are further compromised by surgery and time spent in bed, leading to the death of the patient in a high percentage of cases. The fracture is often spyroid, it has multiple fragments, with interruption of the medial cortical bone. The quality of the bone, because of the marked osteoporosis, does not guarantee the good hold of the means of fixation used. The use of intramedullary nailing is a safe method, that allows for stabilization of the fracture without excessive blood loss, it allows for early partial weight-bearing and it has a lower number of complications as compared to other methods. Between 1-1-97 and 31-12-00 a total of 59 persubtrochanteric fractures were treated; there were 15 males and 44 females. A Gamma Long nail was used in 46 cases, a Gamma Standard in 13. Eleven of the patients died within 6 months. A total of 27 patients aged an average of 78 years (minimum 65, maximum 87) were evaluated at a mean follow-up of 10 months (minimum 7, maximum 27). A Gamma Long nail had been used in 18 cases, and Gamma Standard in 8. Partial weight-bearing was allowed after a mean of 20 days (minimum 10, maximum 35), total weight-bearing after a mean of 60 days (minimum 40, maximum 75). Consolidation was obtained after a mean of 4 months (minimum 3, maximum 7). There were no significant complications.

Renal sinus pseudolymphoma in a patient with multiple carcinomas: a case report and a brief review of the literature.

The term pseudolymphoma refers to a heterogeneous group of benign reactive T-cell or B-cell lymphoproliferative processes of diverse causes that simulate lymphoma clinically and histologically but usually undergo spontaneous remission. Its pathogenesis is still unclear. The prognosis is good although some evidence suggests that pseudolymphoma may progress to lymphoma. Pseudolymphoma of the urinary tract is extremely rare. We herein report a case of pseudolymphoma of the renal sinus in a 70-year-old man, associated with a high grade urothelial carcinoma of the bladder and to a prostatic adenocarcinoma (Gleason score 6). A brief review of the literature is included. The kidney showed a well-defined, whitish soft mass which involved the renal sinus. Microscopically, the lesion of the renal sinus consisted of a proliferation of small to medium size lymphocytes (CD20 positive and Bcl-2 negative) sometimes arranged in hyperplastic follicular structures. The diagnosis was confirmed by molecular studies which showed an oligopolyclonal IgH rearrangement. To the best of our knowledge, this is the second case of pseudolymphoma with a complete molecular characterization ever described in the renal sinus and the first one associated with multiple urogenital carcinomas.