Minimally invasive colon resection for malignant colonic conditions is associated with a transient early increase in plasma sVEGFR1 and a decrease in sVEGFR2 levels after surgery

Introduction  

Plasma VEGF levels increase after minimally invasive colorectal resection (MICR) and remain elevated for 2–4 weeks. VEGF induces physiologic and pathologic angiogenesis by binding to endothelial cell (EC) bound VEGF-Receptor-1 (VEGFR1) and VEGFR2. Soluble forms of these receptors sequester plasma VEGF, decreasing the amount available to bind to EC-bound receptors. Ramifications of surgery-related plasma VEGF changes partially depend on plasma levels of sVEGFR1 and sVEGFR2. This study assessed perioperative sVEGFR1 and sVEGFR2 levels after MICR in patients with colorectal cancer.     

Persistent elevation of plasma vascular endothelial growth factor levels during the first month after minimally invasive colorectal resection

Background Elevations of plasma vascular endothelial growth factor (VEGF) have been noted early after colorectal resection. The duration of this increase is unknown. Because VEGF is a potent promoter of angiogenesis, which is critical to tumor growth, a sustained increase in blood VEGF levels after surgery may stimulate the growth of residual metastases early after surgery. This preliminary study aimed to determine VEGF levels during the first month after colorectal resection. Methods Patients from three prospective studies that had late postoperative blood samples available comprised the study population. Demographic, perioperative, pathologic, and complication data were collected. Plasma samples were obtained preoperatively for all patients: on postoperative day (POD) 1 for most patients and at varying time points thereafter during the first month after surgery and beyond. Levels of VEGF were determined via enzyme-linked immunoassay (ELISA) and compared using Wilcoxon’s matched pairs test. Because the numbers of specimens beyond POD 5 were limited, samples from 7-day time blocks were bundled and averaged to permit statistical analysis. Results A total of 49 patients with cancer and 30 patients with benign indications, all of whom underwent minimally invasive colorectal resection, were assessed separately. With regard to the patients with cancer, the median preoperative plasma value was 150 pg/ml, and the peak postoperative median value for the POD 14 to 20 time block was 611.1 pg/ml. Furthermore, compared with the preoperative results, significant VEGF elevations were noted on POD 3 as well as during week 2 (POD 7–13), week 3 (POD 14–20), and week 4 (POD 21–27) (p < 0.05 for each). With regard to the benign patients, the median preoperative VEGF level was 112 pg/ml, and the peak postoperative value, 286 pg/ml, was noted during postoperative week 2. Significant elevations were noted on POD 3, and for weeks 2 and 3 as well as for POD 28 and later. Between 63% and 89% of the patients at each time point beyond POD 5 had elevated VEGF levels. Conclusion This preliminary study demonstrates that after minimally invasive colorectal resection for cancer, median VEGF levels are significantly elevated on POD 3 and remain increased for as long as 4 weeks. Significant elevations in a similar pattern also were noted for the benign patients. However, the baseline and postoperative median values were lower. The clinical impact from increased blood levels of VEGF is uncertain. It is possible that the growth of residual tumor deposits may be stimulated early after surgery. These results warrant a larger study as well as endothelial cell in vitro assays to determine whether postoperative plasma stimulates proliferation and invasion.     

Influence of postoperative acute-phase response on angiogenesis and tumor growth: Open vs. laparoscopic-assisted surgery in mice

Inflammatory responses and tumor growth are increased after laparotomy compared with laparoscopy in some animal models. Proinflammatory cytokines interleukin-6 (IL-6) and interleukin-1 beta (IL-1β) upregulate the expression of vascular endothelial growth factor (VEGF). Our aim was to investigate the influence of postoperative inflammatory responses on angiogenesis and tumor growth. 5 Χ 10⁶ B51LiM cells were injected into the cecal wall of Balb/c mice. After 2 weeks, the animals were randomized into the following three groups: open cecectomy (OC), CO₂-laparoscopic-assisted cecectomy (LC), and helium-laparoscopic-assisted cecectomy (LH). On postoperative day 12, the mice were killed. Tumor load scores and weight were significantly greater after laparotomy than after laparoscopy. Serum IL-6 levels 6 hours after surgery (OC: 4157 ± 1297 pg/ml vs. LC: 2514 ± 1417 pg/ml vs. LH: 2255 ± 1714 pg/ml) and VEGF levels on postoperative day 12 (OC: 231 ± 125 pg/ml vs. LC: 45 ± 9 pg/ml vs. LH: 49 ± 8 pg/ml), measured by enzyme-linked immunosorbent assay, were significantly higher in the laparotomy group. Microvessel density was also significantly higher in the OC group (OC: 34.3 ± 11.5 vs. LC: 15.5 ± 12.5 vs. LH: 18.5 ± 11.9). There was a positive correlation between IL-6 and VEGF postoperative serum levels (rho = 0.67; P < 0.001). We concluded that increased systemic levels of proinflammatory cytokines and VEGF are associated with increased angiogenesis and tumor growth after laparotomy compared to laparoscopy in mice. Presented at the Fifty-Seventh Annual Sessions of the Owen H. Wangensteen Surgical Forum, The American College of Surgeons Clinical Congress, San Francisco, California, October 6–10, 2002; and published as an abstract in Journal ofthe American College of Surgeons 2002; 195:S69. Supported by an International Fellowship Grant from the American Society of Colon and Rectal Surgeons (M.P.) and by a Postdoctoral Grant (EX2001-35105008) from the Ministry of Education and Culture of Spain.     

Plasma soluble vascular adhesion molecule-1 levels are persistently elevated during the first month after colorectal cancer resection

Introduction

Plasma from the second and third weeks after minimally invasive colorectal resection (MICR) has high levels of the proangiogenic proteins VEGF and angiopoietin 2 and also stimulates, in vitro, endothelial cell (EC) proliferation and migration, which are critical to wound and tumor angiogenesis. Soluble vascular cell adhesion molecule-1 (sVCAM-1) stimulates EC chemotaxis and angiogenesis. The impact of MICR on blood levels of sVCAM-1 is unknown. This study’s purpose was to determine plasma sVCAM-1 levels after MICR in colorectal cancer (CRC) patients.

Methods

Blood samples from 90 patients (26% rectal, 74% colon) were obtained preoperatively, on postoperative days (POD) 1 and 3, and at other points during the next 2?months. The late samples were bundled into 7-day time blocks. sVCAM-1 levels were determined in duplicate via ELISA and reported as ng/ml. Student’s t test was used for data analysis (significance, P?Results The mean incision length was 7.3?±?3.1?cm, and the conversion rate was 3%. Compared with preoperative (PreOp) levels (811.3?±?233.2), the mean plasma sVCAM-1 level was significantly higher on POD 1 (905.7?±?292.4, P?P?Conclusions MICR for CRC is associated with a persistent increase in plasma sVCAM-1 levels during the first month. This sustained increase may promote angiogenesis and stimulate the growth of residual tumor cells early after surgery.     

Colorectal resection,both open and laparoscopic-assisted,in patients with benign indications is associated with proangiogenic changes in plasma angiopoietin 1 and 2 levels

Introduction  Plasma vascular endothelial growth factor (VEGF) levels are increased after surgery and may stimulate tumor growth after cancer resection. Angiopoietin 1 (Ang 1) and Ang 2 are proteins that impact VEGF-related angiogenesis (VRA). Ang 1 stabilizes mature vessels and inhibits VRA, whereas Ang 2 destabilizes vessels and promotes VRA. The ratio of Ang 1 to Ang 2 reflects the net effect; a low ratio promotes VRA. This study’s purpose was to determine the impact of open and minimally invasive (MIS) colorectal resection (CR) for benign indications on plasma Ang 1 and 2 levels. Methods  A total of 30 patients operated by MIS and 26 operated by open procedure were studied. Plasma was obtained preoperatively (PO) and on postoperative days (POD) 1 and 3. Plasma Ang 1 and Ang 2 levels were assessed via enzyme-linked immunosorbent assay (ELISA) in duplicate. Data were compared using Wilcoxon’s matched-pair test and the Mann–Whitney U-test (significance p < 0.05). Results  Indications, types of resection, and morbidity for the groups were similar. The mean MIS incision length was 4.7 ± 1.6 cm while it was 16.8 ± 7.1 cm for the open group (p = 0.0001). For both groups Ang 2 levels were significantly higher and the Ang 1 to Ang 2 ratio was significantly lower on POD 1 and 3 compared with preoperative results. Ang 1 levels were significantly decreased on POD 1 and 3 in the MIS group but only on POD 1 in the open group. For unclear reasons, preoperative Ang 1 levels and Ang 1 to Ang 2 ratios were significantly different between the groups, which precludes comparison of the postoperative results between groups. Conclusion  CR for benign pathology results in higher Ang 2 levels, lower Ang 1 levels, and lower Ang 1 to Ang 2 ratios early after surgery. These alterations are proangiogenic. These results, plus the already noted VEGF increases, suggest that surgery results in proangiogenic plasma protein changes that may stimulate tumor growth early after surgery. The duration of the Ang 1 and 2 changes needs to be determined. An erratum to this article can be found at     

Elevated Serum Vascular Endothelial Growth Factor and Basic Fibroblast Growth Factor Levels in Patients with Thymic Epithelial Neoplasms

Neovascularization, an essential event for the growth of solid tumors, is regulated by a number of angiogenic factors, among which vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), are considered to exert potent angiogenic activity. In this study, we investigated whether serum VEGF and bFGF levels could be predictors of the development and extension of thymic epithelial neoplasms. The subjects of this study were 37 patients with thymoma, 6 with thymic carcinoma, and 23 healthy volunteers. Serum samples were collected before clinical treatment. Serum VEGF levels were significantly (P < 0.05) elevated in the patients with thymic carcinoma (1 080 ± 1 185 pg/ml) compared with those in the healthy volunteers (407 ± 589 pg/ml). Serum bFGF levels were also significantly (P < 0.05) elevated in the patients with thymic carcinoma (2 740 ± 631 pg/ml) compared with those in the healthy volunteers (1 728 ± 1 192 pg/ml). However, the serum VEGF and bFGF levels did not significantly differ between the patients with thymoma and the healthy volunteers. Serum VEGF and bFGF levels did not significantly differ according to the stage and pathological subtype of thymoma. Moreover, there was no correlation between the serum levels of VEGF and those of bFGF. Thus, while serum VEGF and bFGF levels may serve as markers for thymic epithelial tumors, it is unlikely that circulating VEGF and bFGF could be used as markers for assessing the progression of thymoma tumors. Received: November 10, 2000 / Accepted: May 15, 2001     

Plasma levels of angiostatin and endostatin remain unchanged for the first 3?weeks after colorectal cancer surgery

Introduction  

Angiostatin and endostatin are endogenous inhibitors of angiogenesis with anticancer effects. After minimally invasive colorectal resection (MICR), blood levels of the proangiogenic factors vascular endothelial growth factor (VEGF) and angiopoetin 2 (Ang-2) are elevated for 2–4 weeks. Also, postoperative human plasma from weeks 2 and 3 after MICR has been shown to stimulate endothelial cell proliferation and migration, which are critical to angiogenesis. This proangiogenic state may stimulate tumor growth early after MICR. Surgery’s impact on angiostatin and endostatin is unknown. This study’s purpose is to determine perioperative plasma levels of these two proteins in colorectal cancer (CRC) patients undergoing MICR.     

Minimally invasive colon resection is associated with a persistent increase in plasma PlGF levels following cancer resection

Background  

Minimally invasive colorectal resection (MICR) is associated with persistently elevated plasma VEGF levels that may stimulate angiogenesis in residual tumor foci. Placenta growth factor (PlGF) stimulates neovascularization in tumors by modulating VEGF’s effects. This study’s purpose was to determine the impact of MICR on blood PlGF levels in cancer patients (Study A) and to compare PreOp levels in patients with cancer and benign (BEN) disease (Study B).     

Effect of diltiazem on kidney function during laparoscopic surgery

Background  Pneumoperitoneum is known to be associated with transient impairment in kidney function. This study was designed to investigate the effect of diltiazem on acute kidney injury during positive pneumoperitoneum in patients undergoing laparoscopic surgery. Methods  Thirty-two patients of American Society of Anesthesiologists (ASA) 1 and 2 physical status undergoing laparoscopic surgery were randomly divided into control (normal saline infusion) and diltiazem groups (diltiazem 2 μg/kg/min). Urinary flow, urinary sodium excretion, creatinine clearance (CrCl), and hemodynamic variables were determined during pneumoperitoneum and at postoperative 2 h. CrCl using Cockcroft–Gault equation was calculated before surgery (baseline), and at postoperative days 1 (POD1) and 2. Results  The hemodynamic parameters were similar in both groups. CrCl during pneumoperitoneum in the diltiazem group was significantly higher than that in the control group (90.8 ± 49.0 ml/min/1.73 m² vs. 54.2 ± 31.6 ml/min/1.73 m²) (P = 0.026). CrCl calculated with Cockcroft–Gault equation was similar in both groups at baseline, POD1, and POD2. Urinary flow was significantly increased in both groups at postoperative 2 h compared with that during pneumoperitoneum. Conclusion  Continuous infusion of diltiazem 2 μg/kg/min prevented the decrease in CrCl during pneumoperitoneum without hemodynamic derangement. Although the decrease in CrCl was transient in patients with normal kidney function in this study, diltiazem may be used to prevent further kidney injury in those with elevated CrCl during laparoscopic surgery.     

Bone-Resorbing Cytokines from Peripheral Blood Mononuclear Cells after Hormone Replacement Therapy: A Longitudinal Study

Conflicting results have been reported in several cross-sectional studies measuring cytokine production from adherent monocytes in pre- and postmenopausal women. Furthermore, the target cells for the action of estrogen are still debated. We therefore assessed in a longitudinal manner the cytokine production from different fractions of peripheral blood mononuclear cells (PBMC) cultured for 48 h. PBMC were obtained from 30 postmenopausal women before and after 6 months of hormone replacement therapy (HRT). Women were randomly allocated to two groups: an adherent PBMC group (n= 20) and a total PBMC group (n= 9). After 6 months of treatment, urinary pyridinoline levels were markedly decreased in both groups (353 ± 24 vs 114 ± 13 μg/mmol creatinine and 325 ± 35 vs 164 ± 31 μg/mmol creatinine respectively, p<0.01). Culture supernatants were assayed for interleukin 1β (IL-1β), interleukin 6 (IL-6), soluble IL-6 receptor (IL-6rs) and tumor necrosis factor alpha (TNF-α). In the adherent PBMC group, HRT induced a nonsignificant trend toward decreased levels of IL-1β (35 ± 10 vs 13 ± 5 pg/ml), TNF-α (333 ± 58 vs 222 ± 30 pg/ml) and IL-6 (115 ± 70 vs 17 ± 10 pg/ml). In contrast, in the total PBMC group, HRT induced a consistent and dramatic decrease in levels of IL-1β (104 ± 22 vs 25 ± 8 pg/ml), IL-6 (5950 ± 1041 vs 1011 ± 361 pg/ml), IL-6rs (148 ± 33 vs 35 ± 12 pg/ml) (p<0.01) and TNF-α (1468 ± 315 vs 585 ± 207 pg/ml, p= 0.05). We then evaluated whether HRT had the same effect in vitro. Adherent or total PBMC of 8 postmenopausal women were cultured with or without 10⁻⁸M 17β-estradiol or tibolone for 48 h. Production of IL-1β, TNF-α, IL-6 and IL-6rs was not affected by the presence of 17β-estradiol or tibolone in cultures of these cell fractions. In conclusion, our data indicate that non-adherent PBMC could mediate the response to HRT. HRT may exert its action indirectly via noncirculating cells, as suggested by the absence of an in vitro effect. Received: 11 July 2000 / Accepted: 15 January 2001     

Parathyroid Subcutaneous Pre-sternal Transplantation after Parathyroidectomy for Renal Hyperparathyroidism. Long-term Graft Function

Background In the setting of total parathyroidectomy (TPT) and parathyroid transplantation (PTx) for renal hyperparathyroidism (RHP), we evaluated long-term parathyroid graft function after subcutaneous pre-sternal transplantation (SCPTx). Because parathyroid glands are surrounded by fatty tissue, we postulated that results of subcutaneous implantation of parathyroid tissue after total parathyroidectomy for renal hyperparathyroidism could be at least as successful as intramuscular grafting, but without its complications Patients and Methods The study, a prospective open efficacy study of postoperative (po) diagnostic monitoring of intact parathyroid hormone (iPTH) on a cohort of surgical patients, was conducted within a university hospital with a dialysis unit. Thirty five patients (19 women and 16 men) operated on for renal hyperparathyroidism underwent TPT and SCPTx for RHP at the Department of General Surgery and the Department of Nephrology. Donostia Hospital. San Sebastián. Gipuzkoa. Spain, from January 2002 to December 2005. Follow-up ranges from 6 months to 42 months (median: 15.4 months). The main outcome measure was evaluation of graft function by measurement of iPTH plasma level, based on serum levels of iPTH before operation and 24 h and 1, 3, 5, 15, 30, 60, 100, and 150 weeks after surgery Results Average preoperative iPTH values were 1,341.52 + 367.78 pg/ml (mean ± SD) (range: 493–2,180). After TPT and PSCTx, iPTH levels became undetectable in all patients at 24 h. A level of 50 pg/ml was established as the criterion of adequate parathyroid graft function. Values obtained at the various time intervals were as follows: 14.14 + 7.73 1 pg/ml (mean ± SD) (range: 6–36) after 1 week, 53 + 77.33 pg/ml (mean ± SD) (range: 35–74) after 5 weeks, 62.95 + 20.93 pg/ml (mean ± SD) (range: 11–89) after 15 weeks, 77.54 + 18.84 pg/ml (mean ± SD) (range: 24.6–104.2) after 30 weeks, 109.29 + 50.22 pg/ml (mean ± SD) (range: 54–327) after 60 weeks, 134.21 + 128.64 pg/ml (mean ± SD) (range: 43–712) after 100 weeks, and 122.84 + 117.54 pg/ml (mean ± SD) (range: 68–723) after 150 weeks. Prevalence of hypoparathyroidism (intact parathyroid hormone serum level < 20 pg/ml with a normal or low serum calcium concentration) was 2/35 (5.71%) by week 60 and recovered by week 100. Graft-related recurrence was 2.85% (1/35). Conclusions Subcutaneous pre-sternal transplantation (SCPTx) after TPT and PTx for secondary (RHP) is an adequate method to replace muscular forearm parathyroid transplantation and avoid its complications. Functioning results of total parathyroidectomy and presternal subcutaneous grafting compare favorably with the published data on other surgical techniques proposed for the treatment of renal hyperparathyroidism. Results of long-term follow-up exceed previously reported results.     

Urinary interleukin-6 is useful in distinguishing between upper and lower urinary tract infections

This study was designed to determine whether the measurement of interleukin (IL)-6 in urine is useful for distinguishing between acute pyelonephritis and lower urinary tract infection. This observational study was carried out at León Hospital (Spain) on 35 patients (ten boys) aged between 0 and 14 years with urinary tract infection. Urinary levels of IL-6 were determined with enzyme-linked immunosorbent assay (ELISA) at diagnosis and after recovery. Renal dimercaptosuccinate acid (DMSA) scan was performed on all patients to discard or confirm acute pyelonephritis. The mean urinary concentration [x ± standard deviation (SD)] of IL-6 at diagnosis was 20.3 ± 23.3 and 5.3 ± 9.7 pg/ml in patients with acute pyelonephritis and lower urinary infection, respectively [95% confidence interval (CI): 2.6–27.4; p < 0.01]. Specificity for a value of IL-6 >15 pg/ml, was 94.1% (95% CI: 91.1–97.1). Positive predictive value for IL-6 >15 pg/ml was 87.5% (95% CI: 81.1–93.8). IL-6 was undetectable in the urine of both groups of patients at the time of recovery. Urinary levels of IL-6 are useful in differentiating between upper and lower urinary tract infection in children. In this clinical setting, a value >15 pg/ml is a strong indicator of acute pyelonephritis.     

Urinary transforming growth factor beta-1 as a marker of renal dysfunction in sickle cell disease

Renal dysfunction affects 5–18% of patients with sickle cell disease (SCD). To date, no studies have described urinary levels of transforming growth factor β-1 (TGF-β1), a marker of fibrosis, and neutrophil gelatinase-associated lipocalin (NGAL), a marker of acute/chronic kidney disease, as biomarkers in identifying patients at risk of developing renal disease in SCD. We hypothesized that SCD subjects will have increased urinary excretion of TGF-β1 and NGAL compared with healthy controls (CTR). We examined 51 SCD subjects: 42 HbSS, 8 HbSC, and 1 HbSD. Sixteen out of 42 patients with HbSS were on hydroxyurea (HU). Urinary excretion of TGF-β1 was 26.4 ± 1.5 pg/mgCr in SCD subjects vs 15.0 ± 2.4 pg/mgCr in CTR (p < 0.00001). SCD patients with hemoglobin < 9 g/dl had higher urinary TGF-β1 than patients with milder anemia (p = 0.002). Urinary TGF-β1 trended lower in HbSS patients treated with HU (23.61 ± 2.6 pg/mgCr), vs patients not on HU (27.69 ± 1.8 pg/mgCr; p = 0.055). There was no correlation between urinary TGF-β1 and microalbuminuria or estimated glomerular function. There was no difference in urinary NGAL in SCD patients vs CTR. We suggest that urinary TGF-β1 may serve as a marker of early renal injury in SCD.     

Elevated level of endothelin-1 in cerebrospinal fluid and lack of nitric oxide in basilar arterial plasma associated with cerebral vasospasm after subarachnoid haemorrhage in rabbits

Background  The role of endothelin-1 (ET-1) and nitric oxide (NO) as two important mediators in the development of cerebral vasospasm (CVS) after subarachnoid haemorrhage (SAH) is controversial. The objective of this study was to determine whether local levels of ET-1 and NO in cerebral arterial plasma and/or in cerebrospinal fluid (CSF) are associated with the occurrence of CVS after SAH. Methods  CVS was induced using the one-haemorrhage rabbit model and confirmed by digital subtraction angiography of the rabbits’ basilar artery on day 5. Prior to sacrifice, local CSF and basilar arterial plasma samples were obtained by a transclival approach to the basilar artery. Systemic arterial plasma samples were obtained. ET-1 levels were determined by immunometric technique (pg/ml ± SEM) and total nitrate/nitrite level spectrophotometrically (μmol/l ± SEM). Findings  Angiographic CVS was documented after SAH induction (n = 12, P < 0.05). The ET-1 level in CSF was significantly elevated by 27.3% to 0.84 ± 0.08 pg/ml in SAH animals (n = 7) in comparison to controls (0.66 ± 0.04 pg/ml, n = 7, P < 0.05). There was no significant difference in ET-1 levels in systemic and basilar arterial plasma samples of SAH animals compared to controls. A significant lack of local NO metabolites was documented in basilar arterial plasma after SAH (36.8 ± 3.1 μmol/l, n = 6) compared to controls (61.8 ± 6.2 μmol/l, n = 6, P < 0.01). Conclusion  This study demonstrates that an elevated ET-1 level in CSF and local lack of NO in the basilar arterial plasma samples are associated with CVS after experimental SAH.     

Evaluation of a new automated chemiluminescence immunoassay for FGF23

Fibroblast growth factor 23 (FGF23) is a hormone regulating phosphate and vitamin D metabolism. We have previously established a sandwich enzyme-linked immunosorbent assay (ELISA) for FGF23 and reported that FGF23 values are useful for the differential diagnosis of chronic hypophosphatemia. However, this ELISA has a rather narrow assay range of 3–800 pg/ml, and it was pointed out that the assay performance is not satisfactory when automatic washing is used. Here we evaluated a new automated chemiluminescence immunoassay for FGF23. This assay uses 10 μl sera or plasma samples and requires 20 min to obtain the first result. The assay was linear up to about 15,000 pg/ml and had a detection limit of 1 pg/ml. In addition, this assay showed coefficients of variation of less than 5% using samples with average FGF23 levels of 43.2–2,454.0 pg/ml. When FGF23 levels in 210 samples from chronic hypophosphatemic patients were evaluated by both the previous ELISA and this new assay, there was a good correlation of R ² = 0.96. However, FGF23 levels by the new assay showed lower values, especially in samples with high FGF23 levels. Given that the lowest FGF23 level in patients with FGF23-related hypophosphatemia was 30.8 pg/ml and that the highest FGF23 levels in patients with non-FGF23-related hypophosphatemia was 20.8 pg/ml by this novel assay, the sensitivity and specificity were 100% when the cutoff was set between 20.8 and 30.8 pg/ml. From the aspect of convenience and the coefficients of variation of this assay, we propose that the cutoff be 25 pg/ml. There results indicate that this new assay is ideal for both clinical use and clinical studies, especially when measuring many samples with high FGF23 levels.     

Response of different PTH assays to therapy with sevelamer or CaCO<Subscript>3</Subscript> and active vitamin D sterols

Amino-terminally truncated parathyroid hormone (PTH) fragments are detected to differing degrees by first- and second-generation immunometric PTH assays (PTH-IMAs), and acute changes in serum calcium affect the proportion of these fragments in circulation. However, the effect of chronic calcium changes and different vitamin D doses on these PTH measurements remains to be defined. In this study, 60 pediatric dialysis patients, aged 13.9 ± 0.7 years, with secondary hyperparathyroidism were randomized to 8 months of therapy with oral vitamin D combined with either calcium carbonate (CaCO₃) or sevelamer. Serum phosphorus levels did not differ between groups. Serum calcium levels rose from 9.3 ± 0.1 to 9.7 ± 0.1 mg/dl during CaCO₃ therapy (p < 0.01 from baseline) but remained unchanged during sevelamer therapy. In the CaCO₃ and sevelamer groups, baseline serum PTH levels (1st PTH-IMA; Nichols Institute Diagnostics, San Clemente, CA) were 964 ± 75 and 932 ± 89 pg/ml, and levels declined to 491 ± 55 and 543 ± 59 pg/ml, respectively (nonsignificant between groups). Patients treated with sevelamer received higher doses of vitamin D than those treated with CaCO₃. The PTH values obtained by first- and second-generation PTH-IMAs correlated closely throughout therapy and the response of PTH was similar to both PTH-IMAs, despite differences in serum calcium levels.     

Elevated serum pro-MMP2 levels in patients with stage IV thymoma

Abstract. Purpose: There is increasing evidence that matrix metalloproteinases (MMPs) play important roles in tumor invasion and metastasis. Using a one-step sandwich enzyme immunoassay, we investigated whether serum pro-MMP2 levels could be predictors of the development and extension of thymoma. Methods: The subjects of this study were 33 patients with thymoma and 26 patients with nonmalignant thoracic disease. Results: Serum pro-MMP2 levels were elevated in patients with stage IV thymoma (938.6 ± 80.2 ng/ml) compared with those in the controls (P= 0.03). Patients with stage IVb thymoma had significantly higher serum pro-MMP2 levels than patients with other stages, being 1088.7 ± 440 ng/ml in stage IVb, 686.0 ± 74.0 ng/ml in stage I (P= 0.01), 685.8 ± 48.6 ng/ml in stage II (P= 0.01), and 691.7 ± 74.0 ng/ml in stage III (P= 0.02). Serum pro-MMP2 levels were elevated in patients with polygonal cell type thymoma compared with those with mixed cell type thymoma, being 823.1 ± 55.5 ng/ml vs 613.6 ± 59.9 ng/ml, respectively (P= 0.04). Using the reference limit of 850 ng/ml (mean ± 2SD) set from analyses in the control group, all patients who had pro-MMP2 levels below the cutoff level survived. On the other hand, four of nine patients who had an elevated pro-MMP2 level died from recurrence. Conclusion: Serum pro-MMP2 levels may serve as a marker that could be used as an indicator of distant metastases in thymoma. Elevated pro-MMP2 levels may be correlated with poor survival. Received: June 29, 2001 / Accepted: November 20, 2001     

Metabolism of prostaglandins in porcine liver transplantation with a graft harvested after 30- and 60-minute warm ischemia

The influence of warm ischemia on the metabolism of prostaglandins was investigated using a pig liver transplantation model employing the temporary portal arterialization technique. Eighteen pigs were divided into three groups according to warm ischemia time: 0 min (group I,n=6), 30 min (group II,n=6), and 60 min (group III,n=6). During portal arterialization, the hepatic venous prostaglandin E₂ (PGE₂) level in group III (3356.0±1011.8pg/ml) was significantly higher than that in group I (831.7±182.1pg/ml;P=0.0285). The hepatic venous PGE₂ levels were significantly higher than the arterial counterparts in all groups both at the beginning and during portal arterialization. At 60 min after portal revascularization, the arterial PGE₂ level in group III (886.7±268.0pg/ml) was significantly higher than that in groups I (99.0±18.6 pg/ml;P=0.0116) and II (204.2±65.4pg/ml;P=0.0282). Neither thromboxane B₂ (TXB₂) nor 6-keto PGF_1α showed any significant differences. In conclusion, the intra-operative changes of PGE₂ thus reflected the degree of warm ischemic damage, and PGE₂ could also be released from the graft. On the other hand, the increased levels of TXB₂ and 6-keto PGF_1α were throught to have an extrahepatic origin.     

Vitamin D insufficiency and effect of cholecalciferol in children with chronic kidney disease

Vitamin D insufficiency is common in patients with chronic kidney disease (CKD) and may contribute to mineral bone disease. In a prospective interventional study, we estimated the prevalence of vitamin D insufficiency (serum 25-hydroxyvitamin D3 [25OHD] < 30 ng/ml), and examined the effect of high-dose (600,000 IU) cholecalciferol supplementation after 6 weeks on serum 25OHD and parathyroid hormone (PTH) levels in children with CKD stages 2–4. Forty-two children (86% boys) with a mean age of 7.7 ± 3.8 (range 2-–5) years were studied. Thirty-seven children (82.1%) had vitamin D insufficiency; 18 (42.8%) had 25OHD < 16 ng/ml. The median 25OHD increased significantly from 16.7 (95% CI 11.3, 19.8) to 46.2 (34.5, 44.6) ng/ml in patients with vitamin D insufficiency (P <0.001). The median PTH decreased significantly from 51.3 (95% CI 46.7, 71.5) to 37.1 (29.0, 54.6) pg/ml (P = 0.003). Nineteen patients (47.5%) had >30% reduction in the PTH after supplementation. Serum calcium, phosphorus, and estimated GFR did not change significantly. We conclude that vitamin D insufficiency is highly prevalent in children with CKD stages 2–4. High-dose cholecalciferol is safe and effective in correcting vitamin D insufficiency and results in a significant reduction in PTH levels in vitamin D-insufficient children.     

Bone Metabolism and Gonad Function in Male Patients Undergoing Liver Transplantation: A Two-Year Longitudinal Study

Osteodystrophy is a major complication of end-stage liver disease, especially in postmenopausal women. Our aim in this study was to evaluate bone metabolism and gonad function in men undergoing orthotopic liver transplantation (OLTx). Twenty-three consecutive men (mean age 48 ± 13 years) evaluated for OLTx were studied, assessing the following parameters at baseline and 3, 6, 12 and 24 months after OLTx: lumbar spine (L2–L4) bone mineral density (BMD), parathyroid hormone (PTH), osteocalcin (BGP), 25-hydroxyvitamin D (25OHD), free testosterone (FT) and gonadotropins (FSH, LH). At baseline, 12 patients (52%) had a T-score <–2.5 SD and the mean BMD was 0.806 ± 0.11 g/cm² (range 0.470–1.045 g/cm²). The BMD was lower 3 months after OLTx and significantly higher 12 and 24 months after OLTx. A significant increase in serum BGP was observed at 6, 12 (p<0.05) and 24 months (p<0.005) after OLTx. The mean serum PTH level was 26.6 ± 3.1 pg/ml at baseline and increased significantly at 12 and 24 months (to 49.4 ± 9.9 and 61.2 ± 10.1 pg/ml, respectively; p<0.05). 25OHD serum levels were low at baseline and returned to the normal range after 12 and 24 months (baseline, 8.73 ± 1.54 ng/ml; 12 months, 16.4 ± 2.6 ng/ml; 24 months, 17.67 ± 3.1 ng/ml; p<0.05). FT was significantly lower at baseline than in a group of 10 healthy controls (5.09 ± 10.99, vs 10.3 ± 1.1 pg/ml; p<0.0001). After OLTx a significant increase in FT was recorded at 6, 12 (p<0.05) and 24 months (p<0.005). FT was not correlated with BMD, however. After OLTx an increase in FSH and LH was observed (but failed to reach statistical significance) at 3 and 6 months, followed by a slight reduction at 12 and 24 months. Thus a high proportion of men with end-stage liver disease do have osteoporosis. After OLTx, an early recovery of gonad function is observed, followed by an increase in bone mass, which occurs from the sixth month onward. Received: 3 October 2000 / Accepted: 21 March 2001