Perlecan-rich epithelial linings as a background of proliferative potentials of keratocystic odontogenic tumor

Background:  The intraepithelial deposit of perlecan, a basement membrane-type heparan sulfate (HS) proteoglycan, has been demonstrated in neoplastic conditions such as salivary gland tumors, odontogenic tumors, and oral carcinoma in situ . Our aim was to determine whether perlecan turnover was enhanced in the lining cells of keratocystic odontogenic tumor (KCOT), which had been recently renamed from odontogenic keratocyst because of its accumulated evidence of neoplasm, as a possible background for neoplastic proliferation.
Methods:  Ten surgical specimens from each of KCOT, dentigerous cyst, and radicular cyst were examined for the expressions of perlecan core protein, HS chains, heparanase, and Ki-67 by immunohistochemistry and in situ hybridization.
Results:  In KCOT, perlecan core protein and HS chains were localized on the cell border from the parabasal to subkeratinized layers of the lining epithelium. Heparanase was localized in a similar fashion to those for perlecan and HS chains but was within the cytoplasm. mRNA signals for perlecan core protein and heparanase were mostly compatible with their protein signals. Ki-67-positive cells were localized mainly in the second basal cell layers with definitely higher labeling indices (approximately 31.3%, second layer). In contrast to KCOT, dentigerous cysts and radicular cysts had no perlecan, HS chains, and heparanase deposition in their linings with extremely lower Ki-67 indices (0.4–0.8%).
Conclusion:  The result suggests that the characteristic intra-lining-epithelial deposit of perlecan in KCOT, which has never been seen in other cystic jaw lesions, is a new evidence supporting the neoplastic nature of KCOT.     

Calcium supplement necessary to correct hypocalcemia after total parathyroidectomy for renal osteodystrophy

BACKGROUND: Prediction of the extent of calcium supplement will facilitate safe and efficient management of hypocalcemia in the early postoperative stage of total parathyroidectomy with autotransplantation (PTXa) in patients with renal osteodystrophy. METHODS: The correlation between the extent of calcium deficiency, estimated by the amount of calcium supplement over 48 h after PTXa and using various parameters such as carboxy terminal parathyroid hormone (c-PTH), intact PTH (i-PTH), alkaline phosphatase (ALP), serum calcium, serum phosphorus, duration of hemodialysis, total weight of resected parathyroid glands and degree of subperiosteal resorption of the middle phalanx was examined in 49 patients who underwent PTX with subcutaneous autotransplantation. Bone mineral density (BMD) was also determined before, 3 months and 1 year after PTXa with dual energy X-ray absorptiometry (DEXA) in 13 patients. RESULTS: There was a positive correlation between pre-operative i-PTH level (r=0.56, P<0.0005) or ALP level (r=0.50, P<0.0005) and the amount of calcium supplement over 48 h after PTXa in these patients. Furthermore, the degree of subperiosteal resorption, determined by Jensen's classification, was significantly correlated with the amount of calcium supplement after PTX (P<0.05). Bone mineral density 3 months after (P<0.0005) and 1 year after PTXa (P<0.001) significantly increased compared with BMD before PTXa in all patients examined. CONCLUSION: These findings suggest that the pre-operative determination of i-PTH, ALP levels and degree of subperiosteal resorption allow the management of hypocalcemia safely and efficiently in renal osteodystrophy patients after PTXa.     

Combination therapy with an angiotensin-converting enzyme (ACE) inhibitor and a calcium antagonist: beyond the renoprotective effects of ACE inhibitor monotherapy in a spontaneous hypertensive rat with renal ablation.

To assess the renal benefits of combined angiotensin-converting enzyme inhibition and calcium antagonism, we studied the antihypertensive and renoprotective effects of temocapril (TMP) alone or in combination with azelnidipine (AZN) in a spontaneously hypertensive rat (SHR) remnant kidney model of chronic renal failure. Male 5/6-nephrectomized SHR/Izumo rats were randomly assigned to receive vehicle (control group), TMP (TMP group; 10 mg x kg(-1) x day(-1)), AZN (AZN group; 3 mg x kg(-1) x day(-1)), or both (TMP+AZN group) orally for 12 weeks. Systolic blood pressure (SBP) and urinary excretion of albumin (UalbV) were measured every 2 weeks. At the end of the experiment, serum creatinine (Scr), heart weight (HW), and blood urea nitrogen (BUN) levels were measured and the remnant kidneys were examined to determine the index of glomerular sclerosis (IGS). SBP and UalbV in the control group increased progressively throughout the experimental period. TMP, AZN, and TMP+AZN blocked the development of hypertension. TMP+AZN did not enhance the antihypertensive effects of either TMP or AZN used singly. TMP, AZN, and TMP+AZN all significantly decreased the UalbV, Scr, BUN, and HW/body weight (BW) ratio. The level of UalbV and the HW/BW ratio in the TMP+AZN group were significantly lower than those in the TMP and AZN groups, and the level of Scr in the TMP+AZN group was significantly lower than that in the TMP group. TMP, AZN, and TMP+AZN all significantly protected against an increase in the IGS. The IGS in the TMP+AZN group was significantly lower than that in the TMP and AZN groups. These results indicate that both TMP and AZN have antihypertensive and renoprotective effects in this model. They also suggest that simultaneous administration of TMP and AZN provides greater renoprotective effects than TMP alone.     

CHARGE association in a 19-year-old woman

A 19-year-old woman with patent ductus arteriosus, retarded growth, hearing loss, hypoplasia of the uterus, amenorrhea, and normal karyotype was referred to the eye clinic. She had been initially suspected as having Turner syndrome. On examination, optic nerve head coloboma, choroidal coloboma, and microphthalmos were found in the left eye. The diagnosis of CHARGE association was made. Ophthalmologists should be aware of the possible systemic syndrome and its association with coloboma. The authors have stated that they do not have a significant financial interest or other relationship with any product manufacturer or provider of services discussed in this article.     

Higher Frequency of Point Mutations in the c-K-ras2 Gene in Human Colorectal Adenomas with Severe Atypia than in Carcinomas

Human colorectal carcinomas may be induced from adenomas or they may occur de novo. To examine which is the main pathway, we analyzed point mutations at codon 12 in the c-K- ras 2 gene in 73 colorectal carcinomas, 13 metastatic tumors, 72 adenomas and 30 normal tissues. The c-K- ras 2 codon 12 mutation frequency was 0/30 in normal tissues, 0/17 in adenomas with mild atypia, 3/37 (8.1%) in adenomas with moderate atypia, 15/18 (83.3%) in adenomas with severe atypia, 19/73 (26.0%) in primary carcinomas and 3/13 (23.1%) in metastatic tumors. The mutation frequency in adenomas with severe atypia was much higher than that in carcinomas. These results indicate that many colorectal carcinomas may not be induced through adenomas with severe atypia.     

Depth of invasion determines the postresectional prognosis for patients with T1 extrahepatic cholangiocarcinoma

BACKGROUND:

We tested the hypothesis that in patients with T1 extrahepatic cholangiocarcinoma (EHC), prognosis postresection is significantly different for those with tumors that are limited to the mucosa than for those with tumors that have invaded (but not penetrated) the fibromuscular layer.

METHODS:

A retrospective analysis was conducted of 33 consecutive patients with pathologic T1 (pT1) EHC tumors. According to the depth of invasion, the pT1 tumors were divided into 2 groups: Group 1, tumors that were limited to the mucosa (mucosal tumors); and Group 2, tumors that had invaded (but not penetrated) the fibromuscular layer (fibromuscular layer‐invasive tumors). Long‐term outcomes after resection were compared between the 2 groups for a median follow‐up time of 175 months.

RESULTS:

Eighteen patients had mucosal tumors and 15 patients had tumors that had invaded the fibromuscular layer. None of the patients with mucosal tumors had lymphovascular invasion, whereas 3 of the patients with fibromuscular layer‐invasive tumors had lymphovascular invasion (P = .083). Overall survival after resection was better in Group 1 than in Group 2 (cumulative 10‐year survival rate, 100% vs 52%; P = .024). The rate of disease‐free survival after resection was higher in Group 1 than in Group 2 (cumulative disease‐free 10‐year survival rate, 100% vs 56%; P = .022).

CONCLUSIONS:

The long‐term outcome after resection for EHC is significantly better for patients with mucosal tumors than for patients with fibromuscular layer‐invasive tumors. This suggests that the depth of tumor invasion affects the postresection prognosis for patients with pT1 EHC. Cancer 2010. © 2010 American Cancer Society.     

Eradication of Epstein-Barr virus episome and associated inhibition of infected tumor cell growth by adenovirus vector-mediated transduction of dominant-negative EBNA1.

Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA1), a latent viral protein consistently expressed in infected proliferating cells, is essentially required in trans to maintain EBV episomes in cells. We constructed a mutant (mt) EBNA1 and examined whether it exerted dominant-negative effects on maintenance of the viral episome thereby leading to abrogation of EBV-infected tumor cell growth. Using lymphocyte and epithelial cell lines converted with neomycin-resistant recombinant EBV (rEBV) as models, adenovirus vector-mediated transduction of mtEBNA1, but not LacZ, brought about rapid and striking reductions in rEBV-derived wild-type EBNA1 levels and viral genomic loads in converted lines of three major viral latencies. This outcome was further validated at the single-cell level by cellular loss of G418 resistance and viral signals in situ. The mtEBNA1 transduction significantly impaired growth of naturally EBV-harboring Burkitt lymphoma cells in vitro and in vivo, largely in association with the eradication of viral episomes. Expression of mtEBNA1 per se caused no detectable cytotoxicity in EBV-uninfected cells. These results indicate that mtEBNA1 can act as a dominant-negative effector that efficiently impedes the EBV-dependent malignant phenotypes in cells regardless of viral latency or tissue origin. The mutant will afford an additional therapeutic strategy specifically targeting EBV-associated malignancies.     

Upregulation of CD80 on glomerular podocytes plays an important role in development of proteinuria following pig‐to‐baboon xeno‐renal transplantation – an experimental study

We have previously reported that co‐transplantation of the kidney with vascularized donor thymus from α‐1,3‐galactosyltransferase gene knockout pigs with an anti‐CD154 with rituximab‐based regimen led to improved xenograft survival in baboons with donor‐specific unresponsiveness. However, nephrotic syndrome emerged as a complication in which the glomeruli showed mild mesangial expansion with similarities to minimal change disease (MCD) in humans. Since MCD is associated with CD80 expression in glomeruli and elevated urinary excretion, we evaluated a potential role for CD80 in xenograft nephropathy. Study 1 confirmed high urinary CD80 excretion in nephrotic animals with renal xenografts showing CD80 expression in glomeruli. In Study 2, baboons receiving xenografts received CTLA4‐Ig once a week from the second postoperative week or no CTLA4‐Ig. The non‐CTLA4‐Ig group developed severe proteinuria with modest mesangial expansion with high urinary excretion of CD80 and documented CD80 expression in glomerular podocytes. All of the recipients in non‐CTLA4‐Ig groups had to be euthanized before POD 60. In contrast, CTLA4‐Ig group showed a marked reduction in proteinuria and survived significantly longer, up to 193 days. These results demonstrate that anti‐CD80 targeted therapy represents a promising strategy for reduction of proteinuria following renal xeno‐transplantation with improved survival.     

Contrast-enhanced agent detection imaging: Early experience in hepatocellular carcinoma

Purpose: To investigate the usefulness of contrast-enhanced Agent Detection Imaging in assessing intratumoral vasculature in hepatocellular carcinoma.Materials and Methods: Fourteen hepatocellular carcinoma nodules in 11 patients were studied with contrast-enhanced Agent Detection Imaging, a wide-band color Doppler imaging method, employing, Levovist^?, a microbubble contrast agent. High acoustic power was used with contrast-enhanced Agent Detection Imaging. Intermittent transmission of Agent Detection Imaging was performed at intervals of 200, 500, and 350 milliseconds in the early arterial phase (10 to 40 seconds), late vascular phase (1 to 3 minutes) and postvascular phase (5 to 7 minutes), respectively. The results were compared with those of three-phase dynamic CT.Results: Intratumoral blood vessels in the early arterial phase and tumor parenchymal stain in the late vascular phase were depicted in 12 (88%) of the 14 hepatocellular carcinoma nodules, while all nodules were demonstrated as perfusion defect in the postvascular phase on contrast-enhanced Agent Detection Imaging. The results of Agent Detection Imaging, that were compared with those of dynamic CT, were all 100% : diagnostic sensitivity (12/12), specificity (2/2), and accurary (14/14).Conclusion: Contrast-enhanced Agent Detection Imaging is a promising method for depicting intratumoral vascularity in hepatocellular carcinoma.