Phase II study of abarelix depot for androgen independent prostate cancer progression during gonadotropin-releasing hormone agonist therapy

PURPOSE: We determine the clinical efficacy of the gonadotropin-releasing hormone (Gn-RH) antagonist abarelix in patients with androgen independent prostate cancer, and measure its effect on serum follicle-stimulating hormone (FSH) and testosterone. MATERIALS AND METHODS: A total of 20 patients with prostate cancer progression during Gn-RH agonist therapy received 100 mg. abarelix depot by intramuscular injection on days 1, 15 and 29, and then every 28 days for up to 24 weeks. Gn-RH agonist therapy was not continued. Patients who met criteria for prostate specific antigen (PSA) response after 24 weeks of therapy could receive treatment for up to 52 weeks. PSA response was the primary end point and was defined as a 50% decrease confirmed 4 weeks later. Secondary end points of this study were the effect of therapy on serum FSH and testosterone. RESULTS: No patient met the criteria for PSA response. At the end of the 6 cycles of therapy 2 patients remained stable without PSA progression or other signs of disease progression. Median time to progression was 8 weeks (95% CI 5.7-10.3). Mean serum FSH decreased by more than 50% from a baseline of 5.7 IU/l. (95% CI 4.2-7.1) and remained suppressed throughout the observation period. Mean serum testosterone did not change after 4 and 8 weeks of therapy and remained in the anorchid range. Treatment was well tolerated with no grade 3 or higher toxicity. CONCLUSIONS: Treatment of androgen independent prostate cancer with abarelix decreases circulating FSH and maintains anorchid testosterone but does not result in clinical responses.     

Laparoscopic Reoperative Sleeve Gastrectomy for Poor Weight Loss after Biliopancreatic Diversion with Duodenal Switch

Background: The revisional surgery for patients with inadequate weight loss after biliopancreatic diversion with duodenal switch (BPD/DS) is controversial. It has not yet been determined whether a common channel should be shortened or gastric pouch volume reduced. Since the revision of the distal anastomosis remains technically difficult and associated with possible complications, we turned our attention to the reduction of gastric sleeve volume. This operation is more feasible and potential complications are less probable. Patient and Method: We present the case of a 47-year-old women with a life-long history of morbid obesity. She was operated on in January 2000 with a laparoscopic BPD/DS with 100 ml gastric pouch, 150 cm of alimentary limb and 100 cm of common channel. Before this operation, her weight was 170 kg, with BMI 64 kg/m². She lost most of her excess weight within 17 months after surgery and was regaining weight at 77 kg and BMI 29 kg/m². Upper GI series showed a markedly dilated gastric pouch. Her second surgery consisted of a laparoscopic sleeve partial gastrectomy along the greater curvature using endo GIA staplers with bovine pericardium for reinforcement of the stapler line. Results: No postoperative complications occurred. The patient was discharged on the first postoperative day. Significant further weight reduction was noted, and at 10 months after surgery, her weight is 61 kg with BMI 22. Conclusion: A repeat laparoscopic gastric sleeve resection was performed for inadequate weight loss after BPD/DS, and resulted in further weight reduction.     

Semi‐active reduction of vibrations in the mechanical system driven by an electric motor

In this paper, a semi‐active damping approach is used for reduction of vibrations in a laboratory drivetrain system. The considered drivetrain system is powered by an electric, asynchronous motor at the one side and loaded with a harmonically varying torque on the other side. Here, an influence of electromechanical interaction, i.e., an electromechanical coupling, between the electric motor and the mechanical system has been taken into consideration. The harmonic load signal induces torsional vibrations in the system, which in the steady‐state phase of motion become periodic. The aim of the work is to determine the optimal control function for a semi‐active damping element, leading to vibration reduction and considering only the steady‐state phase of system motion. The optimal control is derived by using a semi‐analytical approach based on the optimal control theory aided with supplementary numerical computations. The proposed methodology is fully general, and it can be directly applied to any type of a periodically oscillating system.     

A phase II study of high-dose calcitriol combined with mitoxantrone and prednisone for androgen-independent prostate cancer

OBJECTIVE

To evaluate the preliminary efficacy, safety, and impact on quality of life (QoL) of high‐dose calcitriol (DN‐101) combined with mitoxantrone and glucocorticoids in androgen‐independent prostate cancer (AIPC).

PATIENTS AND METHODS

Nineteen patients with metastatic AIPC and no previous chemotherapy received DN‐101 180 µg orally on day 1 and mitoxantrone 12 mg/m² intravenously on day 2 every 21 days with continuous daily prednisone 10 mg orally for a maximum of 12 cycles. A confirmed decline in prostate‐specific antigen (PSA) levels by half was the primary endpoint. QoL was evaluated using the European Organization for Research and Treatment of Cancer QLQ‐C30 questionnaire, and pain and analgesic use were evaluated.

RESULTS

Five of 19 patients (26%; 95% confidence interval, CI, 9–51) achieved a ≥50% decline in PSA level. The median (95% CI) time to PSA progression was 16 (6–26) weeks. The overall median (95% CI) survival was 16 (6–26) months; 47 (21–73)% of patients achieved an analgesic response. Toxicity was similar to that expected with mitoxantrone and prednisone alone. The QoL analysis suggested a decrease in physical functioning and increase in fatigue, insomnia, and diarrhoea.

CONCLUSIONS

DN‐101 given every 3 weeks does not add significant activity to mitoxantrone and prednisone in AIPC, as measured by the PSA decline. The high rate of analgesic response is encouraging. The addition of DN‐101 does not appear to increase the toxicity of mitoxantrone.     

Value of collagen scaffolds in surgical reconstruction of articular cartilage]

Articular cartilage has a very limited capacity for regeneration and the untreated injuries of this tissue may lead to osteoarthritis. The aim of this study was to evaluate the application of collagen scaffolds in surgical reconstruction of articular cartilage. A group of 28 rabbits was used in the study. A defect penetrating into the subchondral bone was made. The animals were divided into 2 groups: group 1- defects filled with collagen scaffold, group II the defects remained empty. The results were evaluated at 4 a 12 weeks. Macroscopic and microscopic evaluation was performed. On gross examination of the group I complete filling of the defect with regenerated tissue was observed. This tissue had smooth surface and was completely integrated with the surrounding cartilage. In the group II the surface of the newly formed tissue showed large irregularities. The defect was partially filled and incompletely integrated with the residual cartilage. Microscopic results indicate presence of hyaline-like cartilage resembling normal articular cartilage in group I. Regenerate was more stable and remained stable with longer follow-up. Group II revealed mostly fibrous tissue in regenerate. Thickness was inadequate with visible surface irregularities and loss in tissue integrity. This study proved better results of reconstruction of articular cartilage by means of biodegradable scaffold.     

Do preoperative cytokine levels offer a prognostic factor for polypropylene mesh erosion after suburethral sling surgery for stress urinary incontinence?

When polypropylene meshes are used in reconstructive urogynecological surgery, the erosion rates vary from 3.3% to 14% and causative factors for such erosions are still unknown in many cases. Therefore, the aim of our study was to establish the role of immunologic factors in the process of polypropylene tapes erosions after suburethral sling procedures. Serum concentrations of tumor necrosis factor α, interleukin (IL)-2, IL-4, IL-5, IL-10, and interferon (IFN)-γ were estimated in 123 patients suffering from stress urinary incontinence preoperatively and during 12 months follow-up using Human Th1/Th2 Cytokine Cytometric Bead Array I kit. The same immunological assessment was performed in each case of detected tape erosion. Statistical calculation was performed using UNIVARIATE, CORR, and NPAR1WAY procedures from Statistical Analysis System. The unpaired Student’s t test, nonparametric Mann–Whitney U test, and Wilcoxon tests were used. Preoperative IFN-γ concentration was significantly higher in women with subsequent polypropylene mesh erosion when compared to women with successful outcome (p < 0.05). Th1 cytokine profile may be related to the risk of the vaginal erosions following placement of polypropylene meshes. The way to lower erosion rate may involve exclusion of the patients immunologically prone to synthetic material erosion. The factor which can help to select such patients could be preoperative level of IFN-γ.     

Synergistic effect of low dose Cyclosporine A and human interleukin 10 overexpression on acute rejection in rat lung allotransplantation

Objective: Electroporation mediated transfer of plasmid DNA into peripheral muscle results in high transfection efficiency. The aim of this study was to investigate the effect of gene transfer of human IL-10 (hIL-10) into the tibialis anterior muscle (MTA) in combination with low dose Cyclosporine A (CsA) on acute rejection of lung allografts in the rat. Methods: Lung allotransplantation was performed from male BN donor to male Fisher F344 rats. Gene transfer was achieved by intramuscular injection into the MTA of the recipient followed by electroporation (4×20 ms impulses at 200 V/cm) 24 h prior to the transplantation. Group A (n=5) received CsA (2.5 mg/kg bw ip) for 5 days post-transplant and group B (n=5) 2.5 μg of PCIK hIL-10 (plasmid expression vector containing human CMV immediate early gene promoter and enhancer) and a low dose CsA (2.5 mg/kg bw i.p.). Graft function was assessed by blood gas at day 5 after exclusion of the native lung. Animals were sacrificed and blood was drawn to measure serum hIL-10 levels (ELISA) and tissue was sampled for histological grading of rejection. Results: Local expression of hIL-10 was confirmed at the mRNA level by in situ hybridization. All group A control animals showed severe signs of rejection. At day 5 all grafts in group B showed good gas exchange mean PaO2 233±123 mmHg, vs 44±8 mmHg in group A. Histological examination revealed moderate to severe rejection in all animals in group A (IIIB, ISHLT) in contrast to low moderate rejection in group B (II–IIIA). hIL-10 serum levels on day 5 were 14±7 pg/ml in group B vs. 0 in group A. Conclusions: Electroporation mediated hIL-10 overexpression in a peripheral muscle of the recipient in combination with low dose CsA reduces acute rejection in this model of rat lung allotransplantation.     

Interleukin-10 gene polymorphism in Parkinson's disease patients

BACKGROUND: The etiology of sporadic Parkinson's disease (PD) is not well established. Recent studies revealed that inflammatory processes might also play an important role in the pathogenesis of PD. We hypothesized that genetically determined differences in the immune response, especially in anti-inflammatory cytokines production, might influence the risk of sporadic PD development and/or onset. To prove this hypothesis, two DNA polymorphisms at IL-10 promoter (-1082 and -519) were examined in sporadic PD patients. METHODS: The study enrolled 341 patients with diagnosed idiopathic PD. All cases of secondary parkinsonism were excluded from the study. For the purpose of this study the patients were also divided into two subgroups: group 1: patients with onset of Parkinson's disease, i.e., <50 years of age (early onset) included 60 patients, as well as group 2: patients with onset of Parkinson's disease >50 years of age (late onset) comprising 281 subjects. Control samples were from 315 randomly selected healthy individuals from the same geographical region who were free from signs of parkinsonism as evaluated by consultant neurologists. PCR-RFLP methods were used for genotyping. RESULTS: No statistically significant differences between PD patients and controls were found in the frequency of a single locus (-1082, -519) of IL-10 promoter. Likewise, haplotype analysis did not demonstrate any significant differences between evaluated groups. The frequency of the evaluated IL-10 genotypes was also similar in EOPD and LOPD patients. CONCLUSIONS: Results from our study revealed that the IL-10 (-1082G>A, -592C>A) polymorphism is not a risk factor of sporadic Parkinson's disease in a Polish population.     

Vdelta2-Jalpha rearrangements are frequent in precursor-B-acute lymphoblastic leukemia but rare in normal lymphoid cells

The frequently occurring T-cell receptor delta (TCRD) deletions in precursor-B-acute lymphoblastic leukemia (precursor-B-ALL) are assumed to be mainly caused by Vdelta2-Jalpha rearrangements. We designed a multiplex polymerase chain reaction tified clonal Vdelta2-Jalpha rearrangements in 141 of 339 (41%) childhood and 8 of 22 (36%) adult precursor-B-ALL. A significant proportion (44%) of Vdelta2-Jalpha rearrangements in childhood precursor-B-ALL were oligoclonal. Sequence analysis showed preferential usage of the Jalpha29 gene segment in 54% of rearrangements. The remaining Vdelta2-Jalpha rearrangements used 26 other Jalpha segments, which included 2 additional clusters, one involving the most upstream Jalpha segments (ie, Jalpha48 to Jalpha61; 23%) and the second cluster located around the Jalpha9 gene segment (7%). Real-time quantitative PCR studies of normal lymphoid cells showed that Vdelta2 rearrangements to upstream Jalpha segments occurred at low levels in the thymus (10(-2) to 10(-3)) and were rare (generally below 10(-3)) in B-cell precursors and mature T cells. Vdelta2-Jalpha29 rearrangements were virtually absent in normal lymphoid cells. The monoclonal Vdelta2-Jalpha rearrangements in precursor-B-ALL may serve as patient-specific targets for detection of minimal residual disease, because they show high sensitivity (10(-4) or less in most cases) and good stability (88% of rearrangements preserved at relapse).     

Lipoprotein (a) in patients with psoriasis: associations with lipid profiles and disease severity

Background  Lipoprotein (a) [Lp(a)] is a genetically determined molecule whose role has been implied in cardiovascular pathology, and whose levels have been reported to be elevated in patients with psoriasis.
Aim  To assess the serum levels of Lp(a) in patients with psoriasis, and to investigate the associations of Lp(a) with other lipids and with psoriasis severity.
Methods  Thirty-four patients with psoriasis and 26 healthy control subjects took part in the study. Serum levels of Lp(a) and total, high density lipoprotein (HDL), low density lipoprotein (LDL), and very low density lipoprotein (VLDL) cholesterol fractions were measured in all participants. The levels of triglycerides and total cholesterol were measured using enzymatic colorimetric tests; HDL and LDL cholesterol concentrations were determined by precipitation methods; the VLDL concentration was calculated according to the formula: VLDL cholesterol = triglycerides/5.
Results  Patients with psoriasis showed significantly higher serum levels of Lp(a) relative to controls. Even when controlling for normolipidemic vs. hyperlipidemic status, abnormal levels of Lp(a) (> 30 mg/dL) were observed significantly more often in patients than in controls. In both patients and controls, Lp(a) levels correlated positively with total and HDL cholesterol levels. In patients, Lp(a) levels correlated positively with psoriasis severity.
Conclusions  Lp(a) may be a factor contributing to an increased cardiovascular risk in patients with psoriasis. A pathogenetic link may exist between this lipoprotein and psoriatic pathophysiology.