Leptin and prostate cancer

BACKGROUND: Higher prostate cancer mortality rates among US immigrants from countries with lower rates suggest environmental influences on prostate carcinogenesis (e.g., diet, body composition). METHODS: In a study identifying determinants of clinically relevant prostate cancer, we compared plasma concentrations of leptin, an adiposity-related hormone, in 48 men with tumors 0.5 cc in volume or with histologic evidence of extraprostatic extension but without metastases ("high-volume disease"), matched by age (+/- 5 years) and year at diagnosis (+/- 1 year). RESULTS: Men with high-volume disease exhibited higher leptin concentrations overall and after stratification by age, testosterone level, height, and body mass index (BMI). Analysis revealed that men with elevated leptin concentrations had an increased risk of diagnosis with high-volume disease (odds ratio (OR) = 2.35, 95% confidence interval (CI) = 1.01-5.44), as did men with high leptin and high testosterone (OR = 9.73, 95% CI = 2.05-46.24) and men >/=5'8" with high leptin (OR = 3.67, 95% CI = 1.40-9.63). CONCLUSIONS: Leptin may affect the risk of clinically relevant prostate cancer through testosterone and factors related to stature and obesity.     

Increased uncoupling protein-2 levels in beta-cells are associated with impaired glucose-stimulated insulin secretion: mechanism of action

In pancreatic beta-cells, glucose metabolism signals insulin secretion by altering the cellular array of messenger molecules. ATP is particularly important, given its role in regulating cation channel activity, exocytosis, and events dependent upon its hydrolysis. Uncoupling protein (UCP)-2 is proposed to catalyze a mitochondrial inner-membrane H(+) leak that bypasses ATP synthase, thereby reducing cellular ATP content. Previously, we showed that overexpression of UCP-2 suppressed glucose-stimulated insulin secretion (GSIS) in isolated islets (1). The aim of this study was to identify downstream consequences of UCP-2 overexpression and to determine whether insufficient insulin secretion in a diabetic model was correlated with increased endogenous UCP-2 expression. In isolated islets from normal rats, the degree to which GSIS was suppressed was inversely correlated with the amount of UCP-2 expression induced. Depolarizing the islets with KCl or inhibiting ATP-dependent K(+) (K(ATP)) channels with glybenclamide elicited similar insulin secretion in control and UCP-2-overexpressing islets. The glucose-stimulated mitochondrial membrane ((m)) hyperpolarization was reduced in beta-cells overexpressing UCP-2. ATP content of UCP-2-induced islets was reduced by 50%, and there was no change in the efflux of Rb(+) at high versus low glucose concentrations, suggesting that low ATP led to reduced glucose-induced depolarization, thereby causing reduced insulin secretion. Sprague-Dawley rats fed a diet with 40% fat for 3 weeks were glucose intolerant, and in vitro insulin secretion at high glucose was only increased 8.5-fold over basal, compared with 28-fold in control rats. Islet UCP-2 mRNA expression was increased twofold. These studies provide further strong evidence that UCP-2 is an important negative regulator of beta-cell insulin secretion and demonstrate that reduced (m) and increased activity of K(ATP) channels are mechanisms by which UCP-2-mediated effects are mediated. These studies also raise the possibility that a pathological upregulation of UCP-2 expression in the prediabetic state could contribute to the loss of glucose responsiveness observed in obesity-related type 2 diabetes in humans.     

Diversion procto-colitis: response to treatment with short-chain fatty acids

BACKGROUND/PURPOSE: Diversion procto-colitis (DPC) results from a deficiency of luminal short-chain fatty acids (SCFAs). Endoscopic and histopathologic features of the disorder are almost universally present in defunctioned bowel, but symptomatic DPC is less common. METHODS: Five children with symptomatic DPC underwent endoscopy and rectosigmoid biopsies. An endoscopic index (EI) was used to quantify disease severity. An SCFA mixture was administered into the defunctioned bowel. RESULTS: A good clinical response and improvement in the endoscopic index occurred in all children. Undiversion or rectal excision was carried out in 4 and was curative in each case. One child is awaiting a redo pull through. CONCLUSIONS: DPC should be considered in children with a defunctioned colon presenting with evidence of colitis. Histopathology provides supportive evidence and SCFAs may provide effective relief of symptoms. Stoma reversal or rectal excision is curative.     

CD44 enhances tumor formation and lung metastasis in experimental osteosarcoma and is an additional predictor for poor patient outcome

Formation of metastases in the lungs is the major cause of death in patients suffering from osteosarcoma (OS). Metastases at presentation and poor response to preoperative chemotherapy are strong predictors for poor patient outcome. The elucidation of molecular markers that promote metastasis formation and/or chemoresistance is therefore of importance. CD44 is a plasma membrane glycoprotein that binds to the extracellular matrix component hyaluronan (HA) and has been shown to be involved in metastasis formation in a variety of other tumors. Here we investigated the role of CD44 expression on OS tumor formation and metastasis. High CD44 expression, evaluated with a tissue microarray including samples from 53 OS patients and stained with a pan‐CD44 antibody (Hermes3), showed a tendency (p < 0.08) to shortened overall survival. However, nonresponders and patients with lung metastases and high CD44 expression had significantly poorer prognosis than patients with low CD44 expression. Overexpression of the standard CD44 isoform (CD44s) and its HA‐binding defective mutant R41A in osteoblastic SaOS‐2 cells resulted in HA‐independent higher migration rates and increased chemoresistance, partially dependent on HA. In an orthotopic mouse model of OS, overexpression of CD44s in SaOS‐2 cells resulted in an HA‐dependent increased primary tumor formation and increased numbers of micrometastases and macrometastases in the lungs. In conclusion, although CD44 failed to be an independent predictor for patient outcome in this limited cohort of OS patients, increased CD44 expression was associated with even worse survival in patients with chemoresistance and with lung metastases. CD44‐associated chemoresistance was also observed in vitro, and increased formation of lung metastases was found in vivo in SCID mice. © 2013 American Society for Bone and Mineral Research.     

Early changes in scores of chronic damage on transplant kidney protocol biopsies reflect donor characteristics,but not future graft function

The amount of irreversible injury on renal allograft biopsy predicts function, but little is known about the early evolution of this damage. In a single‐center cohort, we examined the relationship between donor‐, recipient‐, and transplantation‐associated factors and change in a morphometric index of chronic damage (ICD) between protocol biopsies performed at implantation and at 2–3 months. We then investigated whether early delta ICD predicted subsequent biochemical outcomes. We found little evidence to support differences between the study group, who had undergone serial biopsies, and a contemporaneous control group, who had not. In allografts with serial biopsies (n = 162), there was an increase in ICD between implantation (median: 2%, IQR:0–8) and 2–3 months post‐transplant (median 8% IQR:4–15; p < 0.0001). Donation from younger or live donors was independently associated with smaller early post‐transplant increases in ICD. There was no evidence for a difference in delta ICD between donation after cardiac death vs. donation after brain death, nor association with length of cold ischemia. After adjustment for GFR at the time of the second biopsy, delta ICD after three months did not predict allograft function at one yr. These findings suggest that graft damage develops shortly after transplantation and reflects donor factors, but does not predict future biochemical outcomes.     

The Effects of Retinoic Acid on the Insulin-like Growth Factor Axis in Primary Tissue Culture from Hyperparathyroidism

Background The importance of the IGF system in HPT has been previously demonstrated. Additionally, the role of vitamin A in HPT has been reported. Retinoic acid (RA), a derivative of vitamin A, is a ligand for the IGF II receptor (IGF2R). We have evaluated the interactions of RA with the IGF system in a primary parathyroid cell culture model. Materials and Methods Primary cell cultures were prepared from nine patients. Following adhesion, the cells were transferred to serum-free medium and dosed once with growth factors ± RA for 96 hours. Proliferation was assessed by measuring tritiated thymidine incorporation. Results Compared with the control group (100%), both IGF I and II increased DNA synthesis significantly. Retinoic acid significantly reduced the basal DNA synthesis to 82.2% ± 4.2% compared with control (P < 0.05). Retinoic acid ×10⁻⁵ M completely abrogated the proliferative actions of IGF II (70.2% ± 9.7%, P < 0.05) but had no significant effect on the IGF I response (P > 0.05). To evaluate the role of IGF2R or IGFBPs in mediating the actions of RA, the IGF II analogs [Leu27]IGF II (10–20-fold reduced IGF I receptor affinity) and des(1–6) IGF II (lower IGFBP binding affinity) were used. The IGF II inhibitory effect of RA was enhanced in the presence of analogs [Leu27]IGF II (P = 0.052) but not with des(1–6)IGF II (P > 0.05), compared with wild-type IGF II. Conclusions These data implicate a novel antiproliferative role for RA in enhancing the pericellular clearance of IGF II via the IGF2R preventing ligand activation of the IGF I receptor. This may have broader implications for RA effects in other tumors.     

Optimizing dose and scheduling of filgrastim (granulocyte colony- stimulating factor) for mobilization and collection of peripheral blood progenitor cells in normal volunteers [see comments]

To define an optimal regimen for mobilizing and collecting peripheral blood progenitor cells (PBPC) for use in allogeneic transplantation, we evaluated the kinetics of mobilization by filgrastim (recombinant met- human granulocyte colony-stimulating factor [r-metHuG-CSF]) in normal volunteers. Filgrastim was injected subcutaneously for up to 10 days at a dose of 3 (n = 10), 5 (n = 5), or 10 micrograms/kg/d (n = 15). A subset of volunteers from each dose cohort underwent a 7L leukapheresis on study day 6 (after 5 days of filgrastim). Granulocyte-macrophage colony-forming cell (GM-CFC) numbers in the blood were maximal after 5 days of filgrastim; a broader peak was evident for CD34+ cells between days 4 and 6. The 95% confidence intervals (CI) for mean number of PBPC per milliliter of blood in the three dose cohorts overlapped on each study day. However, on the peak day, CD34+ cells were significantly higher in the 10 micrograms/kg/d cohort than in a pool of the 3 and 5 micrograms/kg/d cohorts. Mobilization was not significantly influenced by volunteer age or sex. Leukapheresis products obtained at the 10 micrograms/kg/d dose level contained a median GM-CFC number of 93 x 10(4)/kg (range, 50 x 10(4)/kg to 172 x 10(4)/kg). Collections from volunteers receiving lower doses of filgrastim contained a median GM- CFC number of 36 x 10(4)/kg (range, 5 x 10(4)/kg to 204 x 10(4)/kg). The measurement of CD34+ cells per milliliter of blood on the day of leukapheresis predicted the total yield of PBPC in the leukapheresis product (r = .87, P < .0001). Assuming a minimum GM-CFC requirement of 50 x 10(4)/kg (based on our experience with autologous PBPC transplantation), all seven leukapheresis products obtained at the 10 micrograms/kg/d dose level were potentially sufficient for allogeneic transplantation purposes. We conclude that in normal donors, filgrastim 10 micrograms/kg/d for 5 days with a single leukapheresis on the following day is a highly effective regimen for PBPC mobilization and collection. Further studies are required to determine whether PBPC collected with this regimen reliably produce rapid and sustained engraftment in allogeneic recipients.     

Testicular metastasis as the first manifestation of colon carcinoma

Metastatic carcinoma to the testes is uncommon, and it is most often found incidentally at autopsy or after orchiectomy for prostatic carcinoma. One of the rarest causes of testicular tumor is metastasis from another primary site. It is even more unusual when the metastasis to the testicle is the first manifestation of the tumor. We report a case of asymptomatic colon carcinoma presenting as metastases to the testis and epididymis, which was diagnosed after biopsy of testicular nodules. Although nonlymphomatous cancer presenting as an intrascrotal mass is extremely rare, seldom detected clinically and almost never the first sign of disease, it should be considered a possibility, even in the young adult who presents with a mass involving the testicle or epididymis.     

In-111-labeled leukocyte scintigraphy in suspected orthopedic prosthesis infection: comparison with other imaging modalities

When infection of prosthetic orthopedic implants is suspected, optimal management requires accurate confirmation or exclusion of infection. The authors retrospectively studied 98 patients with possible infection who underwent scanning with indium-111-labeled white blood cells (WBCs) and subsequently underwent surgery within 14 days. At surgery, 50 patients had infections, as determined by means of culture or histologic results. The diagnostic accuracy of In-111 scanning was compared with that of plain radiography, arthrography, three-phase bone scanning, and various clinical and laboratory findings classically associated with infection. Positive findings on In-111 WBC scans and elevated erythrocyte sedimentation rates were found to be the most predictive variables in the diagnosis of septic prostheses (P less than or equal to .001 and P less than or equal to .002, respectively). Likelihood ratio analysis more clearly demonstrated the superiority of In-111 WBC scanning, with positive and negative scans yielding likelihood ratios of 5.0 and 0.16, respectively.