Patients' preference of trastuzumab administration (subcutaneous versus intravenous) in HER2-positive metastatic breast cancer: Results of the randomised MetaspHer study.

HannaH (NCT00950300) and PrefHer (NCT01401166) studies validated the subcutaneous (H-s.c.) formulation of trastuzumab as effective and safe as intravenous (H-i.v.) and highly preferred by patients in early breast cancer. The present randomised MetaspHer trial (NCT01810393) is the first study assessing patient's preference in metastatic setting. METHODS: Patients with HER2-positive metastatic breast cancer who completed a first line chemotherapy with trastuzumab and achieved a long-term response lasting more than 3 years were randomised to receive 3 cycles of 600-mg fixed-dose adjuvant H-s.c., followed by 3 cycles of standard H-i.v., or the reverse sequence. Primary end-point was overall preference for H-s.c. or H-i.v. at cycle six, assessed by Patient Preference Questionnaire (PPQ). Secondary end-points included healthcare professional (HCP) satisfaction; safety and tolerability; quality of life. RESULTS: Hundred and thirteen patients were randomised and treated. H-s.c. was preferred by 79/92 evaluable intent-to-treat patients (85.9%, 95% confidence interval [CI; 78.8-93.0]; p < 0.001), 13/92 preferred H-i.v. (14.1%, 95% CI [7.0-21.3]). HCPs were most satisfied with H-s.c. (56/88 available data, 63.6%, [53.6-73.7]). On the safety population, adverse events occurred in 73 (67.6%) and 49 (44.1%) patients during the H-s.c. and H-i.v. periods, respectively; 7 (6.5%) and 4 (3.6%) were grade ≥ III, 3 (2.8%) and 2 (1.8%) were serious. CONCLUSION: The safety was consistent with the known H-i.v. and H-s.c. profiles without safety concern raised. Definitively, patients preferred H-s.c. as reported in early stage by PrefHer study.

Systemic cytokine levels and the effects of etanercept in TNF receptor-associated periodic syndrome (TRAPS) involving a C33Y mutation in TNFRSF1A.

OBJECTIVE: To investigate the levels of the pro-inflammatory cytokines IL-6, TNF-alpha, IL-1beta, IL-8, IL-10 and IL-12p70 in the plasma of patients with TNF receptor-associated periodic syndrome (TRAPS) in relation to CRP levels and treatment with etanercept. METHODS: Cytokine concentrations were measured in sequential plasma samples obtained from eight patients with a C33Y mutation in TNFRSF1A and diagnosed with TRAPS, using cytokine bead array. The TRAPS samples were compared with samples from normal controls and rheumatoid arthritis patients. RESULTS: Levels of IL-6 were significantly elevated in C33Y TRAPS patients and these correlated with CRP levels in some of the patients. IL-8 levels were also significantly elevated in the TRAPS patients. However, neither TNF-alpha nor IL-1beta demonstrated a similar increase. This differed from the patients with rheumatoid arthritis, for whom levels of IL-6, IL-8, TNF-alpha, IL-1beta and IL-10 were significantly elevated. The levels of detectable TNF-alpha in the TRAPS patients' plasma were elevated during etanercept treatment. CONCLUSIONS: The cytokine profile of C33Y TRAPS differs from that of a typical autoimmune inflammatory condition such as rheumatoid arthritis, as only IL-6 and IL-8 were elevated in C33Y TRAPS patients, as distinct from a generalized elevation of pro-inflammatory cytokines. However, only some of the C33Y patients tested showed a relationship between elevated IL-6 and CRP. This is consistent with clinical observations that there is marked heterogeneity between individuals with TRAPS, including those in the same family cohort. Although etanercept has a therapeutic effect in some TRAPS patients, it induces increased plasma concentrations of TNF-alpha, possibly by increasing TNF-alpha stability.

Ultrasound-fluoroscopy guided access to the intrarenal excretory system.

The access to the collecting system can be performed under fluoroscopy computerized tomography, ultrasonographic, mixed ultrasonographic and fluoroscopic guidance. In this paper the creation of a percutaneous transparenchymal ultrasound-fluoroscopy guided access to the intrarenal collecting system completely performed by urologist for different purposes is presented. In five years 297 patients underwent 330 percutaneous kidney accesses to perform derivative nephrostomies (217 pts), percutaneous nephrolithotomies (37 pts), antegrade ureteral manoeuvres (34 pts), antegrade endopyelotomies (7 pts), transitional cell carcinoma of the upper tract resection (2 pts). 11 patients out of these had a percutaneous kidney access in a transplanted kidney. The percutaneous access was successful in 98% of the attemps. A posterior calyx of the lower group (74%), of the medium group (25%) or of the upper group (1%) was accessed. In 73 accesses the mean target calyx diameter was 12.8 mm (range 5-45 mm), the mean operative time 5.4 minutes and the mean fluoroscopy time 5.1 seconds. In 84.5% of the patients the access was performed under local anesthesia when a dilation of the tract was not required. Gross haematuria was observed in 3.9% of the accesses and an arterial lesion treated by embolization in 0.9% of the accesses. Blood transfusion was required in 0.3% of the patients. The ultrasound-fluoroscopy guided access is at least as precise as the fluoroscopy guided one moreover it makes the procedure less invasive and it makes more precise the surgical planning.

Evaluation of urinary level of NMP22 as a diagnostic marker for stage pTa-pT1 bladder cancer: comparison with urinary cytology and BTA test.

BACKGROUND: In the present study we compared the clinical value of two new specific tests for transitional cell carcinoma, urinary nuclear matrix protein (NMP22) levels and bladder tumor antigen (BTA) test, with that of urinary cytology in the follow-up of patients with superficial bladder cancer. MATERIALS AND METHODS: Hundred and five bladder cancer patients were recruited: 30 stage pTa and 45 stage pT1 (group A), and 30 with a history of bladder cancer but no recurrence at the time of the study (group B). Urine samples were collected before any instrumental manipulation of the genitourinary tract. All patients were negative for urinary tract infections at conventional urine analysis. RESULTS: NMP22 at a cutoff value of 6 U/ml showed a sensitivity of 83.3% in pTa cases and 97.7% in pT1 cases, with a false-positive rate of 23.3%. The BTA test was positive in 26.6% of patients with cancer stage pTa and in 66.6% of pT1 stage, with 30% false-positives in the non-neoplastic group. Urinary cytology, performed on three consecutive samples, was positive in 20% of patients with cancer stage pTa and in 64.4% of pT1 stage and did not show any false-positive cases. Stratifying the neoplastic patients according to lesion grade, NMP22 (at a cutoff value of 6 U/ml) was positive in 86.2% of G1, 97.2% of G2 and 90% of G3. BTA was positive in 37.9, 52.7 and 70% of G1, G2 and G3, respectively, while urinary cytology was positive in 37.9, 44.4 and 80%.

Toxicity of dopamine and dopaminochrome on cultured cells.

Cultured rat fibroblasts, monkey kidney tumor cells (line Vero) and murine neuroblastoma cells were exposed to dopamine or dopaminochrome in the presence and absence of ascorbic acid. Ascorbic acid is able to potentiate the toxicity of both dopamine and dopaminochrome for all the tested cells. The toxicity of dopaminochrome was higher than that of dopamine. There is a correlation between toxicity and levels of bioreductive defenses of the cells, e.g. DT-diaphorase (NAD(P)H:quinone oxidoreductase EC 1.6.99.2) and glutathione. In general, tumor cells have lower defenses and seem to be more sensitive to the toxic action.

[Conservative treatment of renal cell carcinoma: framework, incidence and classification]. / La terapia conservativa nel carcinoma renale: inquadramento, incidenza e classificazione.

Recent interest in nephron sparing surgery for renal cell carcinoma has been stimulated by advances in diagnostic imaging, following an increasing number of incidentally discovered low stage renal cell carcinoma and good long term survival in patients undergoing this form of treatment. Tosaka et al reported a 5-years survival of 94.7% in patients with incidental renal cell carcinoma compared with 60.9% in diagnosed because symptomatic. Along with a diagnosis of carcinoma more and more premature, a whole string of little lesions is present, not easily identifiable by the recent diagnostic imaging. Tosaka and others examined renal lesions going by the ultrasonography as a check-up or as a first frame in patients suffering from microscopic hematuria; they proved that neoplastic lesions represent 5.4% of all the masses identifiable by diagnostic imaging. The frequent discovery of limited carcinoma, the difficulty in the diagnostic attribution and demonstration of the good survival of patients who were treated by a nephron sparing surgery, added to the one of patients undergone to radical nephrectomy, caused an interest in nephron-sparing surgery for incidental renal carcinoma also for patients with normal controlateral kidney and not very extended tumors, usually in peripheral sites. At the moment record of cases concerning nephron sparing surgery is quite limited, any way it shows a survival equal to 90% with only two local recurrences, reported only in one experience and caused by an incomplete resection or by multicentric neoplastic lesions.

The proline-rich region of the GH receptor is essential for JAK2 phosphorylation, activation of cell proliferation, and gene transcription.

Mutational analysis of the proximal transmembrane region of the cytoplasmic domain of the GH receptor (GHR) allowed us to characterize box 1, a proline-rich sequence of eight amino acids, which has been shown to be critical for signal transduction of many cytokine receptors. Mutants of the box 1 region of the rat GHR were studied for their ability to initiate the phosphorylation of JAK2 and the proliferation of stably transfected BAF B03 cells and also the activation of Spi 2.1 gene transcription in transiently transfected Chinese hamster ovary (CHO) cells. Convergence of effects of the box 1 mutants on JAK 2 phosphorylation, cell proliferation, and gene transcription was found. Our results suggest that no single amino acid in the box 1 sequence is essential for signaling and that the last two prolines (PXP motif) and the hydrophobic residues are necessary for integrity of box 1. Box 1 represents a structural determinant, potentially able to provide an interaction between JAK2 and the receptor; this interaction could be direct or indirect via an adaptor protein.

Expression of two isoforms of the human growth hormone receptor in normal liver and hepatocarcinoma.

In man, two isoforms of growth hormone receptor (GHR) have been reported. The first, hGHR corresponds to the original form described by Leung et al. (J. Biol. Chem. 264 (1987) 9905-9910). The second, hGHRd3, missing 22 N-terminal amino acids is encoded by an mRNA derived from alternative splicing and deletion of the third exon. This latter form has been isolated from placenta and its tissue distribution, as well its function warrant further examination. We studied the relative expression of the two isoforms of GHR in liver at various stages of development of differentiation. Several samples from fetal livers and hepatocarcinomas were analysed and we observed that hGHR and hGHRd3 can be expressed solely or coordinately. Furthermore, we investigated the possibility that alternative splicing of exon 3 could be related to the specific use of different promoters. Our data show that both isoforms have identical 5'-untranslated regions in normal liver or in hepatoma cell lines. Finally, these experiments strongly suggest that hGHRd3 is efficiently translated as a functional receptor, with the soluble form of GHR being recovered in the cell media. The results of the present study support the concept that both isoforms are expressed in human liver, with exon 3 alternative splicing being neither tissue specific nor related to hepatic differentiation.

Modifications of cell-cycle induced by dpr, a new platinum-triamine complex containing procaine.

cis-diamminechloro-[2-(diethylamino)ethyl 4-amino-benzoate, N4]-chlorideplatinum(II) monohydrochloride monohydrate (DPR) is a new platinum-triamine complex containing as ligand the local anesthetic procaine. In this study DPR was compared to the parent compound cisplatin (cis-DDP) in order to study the influence of both molecules on the cell cycle phases, and particularly on the induction of apoptosis. P388 murine leukemic cells were used as cellular model, and were exposed in vitro to either compound, continuously for 24 hours. At the end of the incubation, the thymidine uptake, the trypan blue dye exclusion assay, and the flow cytometry were assessed. Both the cytotoxic activity and the inhibition of DNA synthesis evaluated after 24 h incubation with DPR or cis-DDP were comparable. Moreover, cell cycle was modified in a comparable manner by both molecules. In particular the induction of the apoptotic effect was similarly induced by the same concentrations of the compounds and time exposure. In conclusion, DPR and cis-DDP seem to have a similar effect on the cell cycle of P388 leukemic cells and particularly on the induction of the programmed cell death.