Testosterone Concentrations and Sirolimus in Male Renal Transplant Patients

Sirolimus damages the testes in animals; however, human data are sparse. We conducted a case-control study to obtain further insight into this issue and compared testosterone, follicle-stimulating hormone (FSH), luteinizing hormone (LH), and prolactin concentrations in matched renal transplant patients who did or did not receive sirolimus. We found that testosterone values were lower (11.2 +/- 6.3 nmol/L vs. 15.5 +/- 7.7 nmol/L, p < 0.05), in 28 sirolimus-treated patients, compared to 28 non-sirolimus-treated controls. Furthermore, these patients more commonly had testosterone concentrations that were below our reference value for normal men. In contrast, FSH and LH concentrations were higher while prolactin levels were not different. These data are consistent with sirolimus-related testosterone suppression and suggest a need for further studies.     

Increasing mastectomy rates among all age groups for early stage breast cancer: a 10-year study of surgical choice

First-line surgical options for early stage breast cancer and ductal carcinoma in situ include breast conserving surgery or mastectomy. We analyzed factors that influence the receipt of mastectomy and resultant trends over time. Registry analysis was carried out for 21,869 women who underwent up-front surgical treatment for stage 0, I or II breast cancer between 1998 and 2007 using data from the Kentucky Cancer Registry. We examined the trend of treatment over time and assessed the probability of receiving mastectomy using multivariate logistic regression. Overall, 54.5% of women received breast conservation and 45.5% received mastectomy over a 10-year period (annual BCS rate range: 46.9-61.2%). The overall mastectomy rate substantially decreased from 53.1% in 1998 to 38.8% in 2005 (p < 0.0001), but then increased to 45% in 2007 (p < 0.001). Between 2005 and 2007, the increase in mastectomies in the age groups of <50 years, 50-69 years, and ≥ 70 years was 7.5% (p = 0.0351), 4.9% (p = 0.0132) and, 8.0% (p = 0.0283), respectively. On multivariate analysis, the rate of receiving mastectomy was drastically higher for women with stage I or II (versus in situ) disease and moderate or poorly differentiated (versus well differentiated) histology. The rate was modestly higher for uninsured and government-insured (versus privately insured) patients, patients older than 70 years (versus younger), rural (versus urban) location, receptor negative (versus receptor positive) disease, and unusual histologies (versus ductal and lobular histology). There was no statistically significant difference in surgical choice with regard to race. Determinants of mastectomy for in situ and early stage breast cancer include stage, histology, age, insurance status, county of residence, receptor status. The rate of mastectomy declined until 2005 and is now increasing across all age groups, especially for women < 50 years and ≥ 70 years.     

A phase Ib/II and pharmacokinetic study of EP0057 (formerly CRLX101) in combination with weekly paclitaxel in patients with recurrent or persistent epithelial ovarian,fallopian tube,or primary peritoneal cancer

Background: EP0057 (formerly CRLX101) is an investigational nanoparticle-drug conjugate (NDC) of a cyclodextrin-based polymer backbone plus camptothecin, a topoisomerase-1 inhibitor. Prior studies showed efficacy in recurrent or persistent, epithelial ovarian, fallopian tube or primary peritoneal cancer (EOC).Methods: This phase Ib/2 trial assessed safety and efficacy of EP0057 Q2W plus weekly paclitaxel in patients with EOC. The recommended phase 2 dose (RP2D) was identified using a 3+3 design. The single-arm phase 2 assessed overall response (ORR) per RECIST 1.1 in patients previously treated with bevacizumab. Secondary objectives included progression free survival (PFS) and duration of response.Results: The RP2D was established as 15 mg/m² EP0057 Q2W plus 80 mg/m² paclitaxel administered 3 weeks on/1 week off. Nine patients enrolled on phase 1b, with no DLTs; 21 additional patients enrolled on phase 2. All completed >1 cycle. Median age was 62 (44-76) years, 57% ≥3 prior therapies. For the primary analysis, 6/19 patients with prior bevacizumab had confirmed responses (ORR=31.6% (95% CI: 15.4% to 54.0%)) including one complete response (CR). Median PFS was 5.4 months. Most common grade 3/4 adverse events attributed to treatment were decreased neutrophil count (13, 43%) and anemia (3, 10%).Conclusions: Although the observed ORR was not statistically better than the historical control rate, EP0057 remains an interesting option for treatment of recurrent EOC. EP0057 exhibits high plasma drug retention, slow clearance, and controlled slow release of CPT from the polymer when administered alone and with paclitaxel. (NCT02389985) 242 words     

Frequent intravenous pulses of growth hormone together with alanylglutamine supplementation in prolonged critical illness after multiple trauma: effects on glucose control, plasma IGF-I and glutamine.

OBJECTIVE: We aim to demonstrate that low dose growth hormone (GH) administered in i.v. pulses every 3h is able to normalize IGF-I levels in subjects with prolonged critical illness, after multiple trauma. We also ask whether it is possible to control glycaemia during such a treatment and how alanylglutamine (AG) supplementation influences plasma glutamine concentration. METHODS: We used a prospective double-blind (group 1 vs. 2), randomized trial with an open-label control arm (group 3). Thirty multiple trauma patients (median age: 36, 42, 46 years) were randomized on day 4 after trauma to receive (group 1, n=10) i.v. AG supplementation (0.3 g/kg day from day 4 till 17) and i.v. GH (0.05 mg/kg day divided into 8 boluses, maximum dose at 3 AM, administered on days 7-17) or AG and placebo (group 2, n=10). Group 3 (n=10) received isocaloric isonitrogenous (proteins 1.5 g/kg day) nutrition without AG. Glycaemia was controlled by i.v. insulin infusion according to a routine protocol. RESULTS: GH treatment caused an increase of IGF-I (from median 169 on day 4 to 493 ng/ml on day 17), IGFBP-3 (from 2.4 to 3.2 microg/ml) and a fall in IGFBP-1 (from 11.5 to 3.1 microg/ml), whilst in both groups 2 and 3 these indices remained unchanged. At the end of the study (day 17) IGF-I and IGFBP-1 differed significantly among groups (p=0.008 resp. p=0.010, Kruskal-Wallis). Plasma glutamine remained below the normal range through the study in all groups (median: 0.18-0.30 mM), but had a tendency to rise in group 2 in contrast with a fall in groups 1 and 3 (NS). Group 1 required more insulin (p<0.01) than did the control group but median glycaemia was only 0.4-0.5 mM higher in group 1 (6.5 mM) than in groups 2 and 3 (6.1 resp. 6.0 mM). CONCLUSIONS: GH (0.05 g/kg day) administered in i.v. pulses is able to normalize IGF-I levels in subjects with prolonged critical illness after trauma. During this treatment, the standard dose of AG prevents worsening of plasma glutamine deficiency and glucose control is possible using routine algorithms, but it requires higher insulin doses.     

Melanotic xp11.2 neoplasm of the ovary: report of a unique case

We describe a primary ovarian neoplasm, occurring in a 15-year-old female patient, with morphologic, immunohistochemical, and molecular genetic features identical to those of the very rare tumors of the kidney previously described as "melanotic Xp11 translocation renal cancer." This represents, to the best of our knowledge, the first report of a melanotic Xp11 translocation-associated neoplasm arising outside of the kidney. We discuss the relationship of these rare tumors to neoplasms showing perivascular epithelioid cell differentiation, in particular those showing TFE3 rearrangements.     

Scintigraphic imaging of the heart in dogs damaged by irradiation

The paper verified literature data assuming that the heart damage caused by irradiation of thorax may be scintigraphically detected by means of 99mTc-pyrophosphate. Three dogs underwent a single irradiation of thorax with a gamma cobalt source by the Dose 40 Gy. The myocardium scan was performed 24 hours, 20 days, 50 days, 80 days and 93 days after the irradiation. The scintigraphic examination proved to be negative at all the intervals observed. A comparison of the scan with morphological findings and with radioactivity of tissue samples after the dogs were sacrificed 93 days after the irradiation proved that the negativity of the pyrophosphate scintigraphy was caused by a minimum damage of the myocardium and not by an inability of 99mTc-pyrophosphate to be incorporated into radiation lesions. The data in literature on myocardium damage by irradiation appear to be considerably exaggerated.     

Effect of mycophenolate mofetil on rat kidney grafts with prolonged cold preservation

The impact of mycophenolate mofetil (MMF) on initial renal transplant function is not well characterized. We tested how MMF may modulate graft function and survival in a syngeneic rat kidney transplantation model after prolonged cold preservation. Donor kidneys were preserved in University of Wisconsin for either 24 or 39 h prior to transplantation into nephrectomized rats. Recipients received MMF (20 mg/kg/day) or vehicle. Mycophenolic acid (MPA) blood concentrations were measured by high-performance liquid chromatography. The inflammatory response, tubular epithelial proliferation, and histologic damage 3 days post-transplantation were assessed microscopically. In the 24 h cold storage (c.s.) group serum-creatinine was measured. In the 39 h c.s. group 1-week recipient survival was determined. After 24 h of c.s., recipient survival was 100%. The number of T-cell infiltrates was low and not influenced by MMF, whereas renal ED1+ cell infiltration was significantly suppressed by MMF. Tubular cell proliferation was enhanced by MMF. Serum-creatinine levels and renal histology were comparable between MMF and vehicle-treated animals. In the 39 h c.s. group, recipient survival was 20% in MMF-treated vs 90% in vehicle-treated animals (P=0.001). MMF effectively suppressed inflammatory cell infiltration and inhibited tubular cell proliferation. MMF-induced structural damage was most striking in the renal papilla. In rat kidney grafts with moderate preservation injury (24 h c.s.), MMF, given at an immunosuppressive dose, showed predominantly antiinflammatory effects without compromising graft function. In grafts with severe preservation injury (39 h c.s.), MMF caused irreversible structural damage and inhibited tubular cell regeneration resulting in renal failure.     

Advances in the surgical management of ovarian cancer

Over the past 10 years, significant advances have been made in the treatment of epithelial ovarian cancer in the United States. Women are living longer with ovarian cancer, and the survival for all cases in the U.S. has increased. Some, but not all, of this success is secondary to new surgical approaches. New techniques, new philosophies and new technology have changed the surgical approach to ovarian cancer in a variety of clinical situations, and these changes have affected the care of women with ovarian cancer. Access to specialist surgeons continues to be very important in the care of women with ovarian cancer to ensure adequate staging, optimal cytoreduction and application of secondary cytoreduction when appropriate. Further work needs to be undertaken in screening, prevention, surgery and adjuvant therapy.