Kyungji Lee

The short-term changes of bone mineral metabolism following bone marrow transplantation

Organ transplantation is now the treatment of choice for many patients with life-threatening chronic diseases. A new set of side effects unique to these groups of patients has become recognized, and bone disease is one of these complications. However, little is known about the effects of myeloablative treatment followed by bone marrow transplantation (BMT) on bone mineral metabolism. We have prospectively investigated 31 patients undergoing BMT for hematologic diseases. Serum concentrations of calcium, phosphorus, creatinine, gonadotropins, sex hormones, and the biochemical markers of bone turnover were measured. The samples were collected before BMT and 1, 2, 3, 4, and 12 weeks, 6 months, and 1 year after BMT. Bone mineral density (BMD) was measured with dual-energy X-ray absorptiometry before BMT and 1 year after BMT. The serum carboxy-terminal cross-linked telopeptide of type I collagen increased progressively until 4 weeks after BMT. Thereafter, it began to decrease and reached basal values after 1 year. Serum osteocalcin decreased progressively until 3 weeks after BMT. After that, it increased and reached basal values after 3 months. No distinct differences were observed in the serum biochemical turnover markers between males and females, or between patients who received total body irradiation and those who did not. One year after BMT, lumbar spine BMD had decreased by 2.2%, and total proximal femoral BMD had decreased by 6.2%. Eighty-six percent of the women (12/14) went into a menopausal state immediately after BMT. This was caused by high gonadotropin levels and low estradiol levels. In contrast, gonadotropin levels and testosterone levels did not change significantly in the male patients after BMT. In conclusion, the rapid impairment of bone formation and the increase in bone resorption, as shown by the biochemical markers in this study, might play a role in post-BMT bone loss.

The Role of Cytokines in the Changes in Bone Turnover Following Bone Marrow Transplantation

Abstract: Osteoporosis is a common disease among patients undergoing transplantation and a loss of bone mass is usually detected after bone marrow transplantation (BMT), particularly during the immediate post-BMT period. Post-BMT bone loss is primarily related to gonadal dysfunction and immunosuppression. Cytokines, especially interleukin 6, play an important role in the pathogenesis of postmenopausal osteoporosis. However, the pathogenetic role of cytokines in post-BMT bone loss is unknown and data on the changes of cytokines in accordance with bone turnover markers are scarce. The aim of this study was to assess the relationship between bone turnover markers and cytokines, which are regularly sampled at peripheral blood and bone marrow before and after allogeneic BMT. This prospective study included two analyses. The first was a study of 46 BMT recipients (M/F 28/18), examining the relationship between bone turnover markers and serum cytokines that were measured before and at 1 week, 2 weeks, 3 weeks, 4 weeks and 3 months after BMT. Serum intact parathyroid hormone was measured before BMT and at 3 weeks after BMT and its relation to other cytokines and bone turnover markers was evaluated. The second analysis was a study of 14 (M/F 9/5) of 46 patients in whom bone marrow plasma cytokines [interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α)] were measured at 3 weeks after BMT. The relationship between bone marrow plasma cytokines and bone turnover markers was studied because bone marrow is the microenvironment where the real changes in bone turnover occur. Serum type I collagen carboxyterminal telopeptide (ICTP), a bone resorption marker, increased progressively until 4 weeks (peak) after BMT and then decreased thereafter. Serum osteocalcin, a bone formation marker, decreased progressively until 3 weeks after BMT and then increased thereafter. Serum IL-6 increased until 2 weeks after BMT and declined thereafter. Serum TNF-a increased until 3 weeks after BMT and declined thereafter. There was a significant positive correlation between serum ICTP and bone marrow IL-6 levels at 3 weeks after BMT, when a marked change in bone metabolism occurs following BMT. However, a correlation between bone turnover markers and bone marrow TNF-aor peripheral blood cytokines was not found. At 3 months after BMT, there was a significant negative correlation between the mean daily steroid dose and the serum osteocalcin level (r=−0.43, p<0.05). The correlation between the mean daily steroid dose and serum ICTP was also significant (r= 0.41, p<0.05). Our data suggest that the progressive increase in bone resorption during the immediate post-BMT period is related to both steroid dose and the increase in bone marrow IL-6, which is a potent stimulator of bone resorption in vivo.

Gallbladder wall thickening: MR imaging and pathologic correlation with emphasis on layered pattern.

The aim of this study was to correlate MR findings of gallbladder wall thickening with pathologic findings on the basis of the layered pattern and to evaluate the diagnostic value of MR imaging in gallbladder disease. We retrospectively evaluated the source images of HASTE sequences for MR cholangiography in 144 patients with gallbladder wall thickening. The layered pattern of thickened wall was classified into four patterns. Type 1 shows two layers with a thin hypointense inner layer and thick hyperintense outer layer. Type 2 has two layers of ill-defined margin. Type 3 shows multiple hyperintense cystic spaces in the wall. Type 4 shows diffuse nodular thickening without layering. MR findings of a layered pattern of thickened gallbladder were well correlated with histopathology. Chronic cholecystitis matched to type 1, acute cholecystitis corresponded to type 2, adenomyomatosis showed type 3, and the gallbladder carcinomas showed type 4. All four layered patterns were associated with PPV of 73% or greater, sensitivity of 92% or greater and specificity of 95% or greater. Our results indicate that MR findings of gallbladder wall thickening are characteristic in each entity and correlate well with pathologic findings. The classification of the layered pattern may be valuable for interpreting thickened gallbladder wall.

Impact of circulating bone-resorbing cytokines on the subsequent bone loss following bone marrow transplantation

Summary:Cytokines including IL-6 and TNF-α play an important role in the pathogenesis of postmenopausal osteoporosis. However, the relationship between changes in the cytokine levels and subsequent bone loss in patients undergoing a bone marrow transplantation (BMT) is unclear. A total of 46 patients undergoing an allogeneic BMT were prospectively investigated. The bone turnover markers and the serum cytokines were measured before BMT and serially after BMT. Bone mineral density (BMD) was measured before and 1 year after BMT. At 1 year after BMT, the lumbar spine BMD had decreased by 4.8%, and the total proximal femoral BMD had decreased by 12.3%. The serum IL-6 and TNF-α levels increased until 2 and 3 weeks after BMT, respectively. The lumbar BMD was significantly decreased as the serum IL-6 and TNF-α levels increased by post-BMT 3 weeks. The lumbar BMD decreased significantly as the cumulative prednisolone and cyclosporine dose increased. Patients with GVHD ⩾grade II had higher lumbar bone loss than patients with GVHD <grade I. In conclusion, immunosuppressants, GVHD occurrence and increase in bone-resorbing cytokines in the early post-BMT period were associated with later bone loss after BMT. Further studies are needed to elucidate the precise mechanism.

Loss of beta-cells with fibrotic islet destruction in type 2 diabetes mellitus.

Recent morphologic analyses of human pancreases strongly suggest that a decreased beta-cell mass is observed from the early stages of diabetes and is caused by accelerated apoptosis of the beta-cells. In this article, we propose that fibrotic islet destruction might be one of the important pathogenic mechanisms of the limited capacity of beta-cell proliferation and accelerated apoptosis in diabetic patients. We have found that pancreatic stellate cells (PSCs) are involved in the progression of islet fibrosis in type 2 diabetes. High concentrations of glucose and insulin in islets contribute to PSC activation and proliferation through angiotensin II type 2 (ATII) signaling pathway, although the exact mechanisms remain to be confirmed. Angiotensin-converting enzyme inhibitors attenuate fibrotic islet destructions and that these have some beneficial effects on glucose tolerance. We suggest that PSCs might play a major role for the fibrotic islet destruction in patients with type 2 diabetes, and suppression of PSCs activation and proliferation might be one of the reasonable target to prevent and delay the progression of the type 2 diabetes mellitus.

Expression of HPV L1 capsid protein in cervical specimens with HPV infection

We tried to investigate the expression rate of human papillomavirus (HPV) L1 capsid protein in uterine cervical specimens and correlate it with the grade of dysplasia, HPV genotype and age of the patients. Among uterine cervical specimens proved to have HPV by DNA genotyping test, eighty cytology‐biopsy matched cases and 22 unmatched cytology specimens were selected. Immunostaining for L1 capsid protein was performed on both cervical smears and tissue sections. The L1 capsid protein was expressed mainly in the nuclei, but occasionally in the cytoplasm of cells located in the superficial layer of squamous epithelium. The immunostaining for L1 capsid protein showed positive reaction in 47 cases (46.1%) of cervical smears and in 10 cases (12.5%) of tissue sections (P = 0.001). Cytologic diagnosis revealed a higher expression rate in LSILs (25/33; 75.8%) than in HSILs and cervical cancers (8/20; 40.0% and 2/5; 40%, respectively) (P = 0.006). In LSILs, cases with low‐risk type HPV showed a higher L1 capsid expression rate than those with the high‐risk type HPV (88.9% vs. 70.8%). The L1 capsid expression rate decreased in the over‐40‐year‐old age group compared to the younger age (49.2% vs. 50.8%). Cytology smears were superior to tissue sections for the detection of L1 capsid protein expression. LSILs and HPV low‐risk group showed higher L1 capsid expression rate than HSILs and HPV high‐risk group, which suggests that L1 capsid expression might be related to a favorable disease biology. Diagn. Cytopathol. 2008.

Expression of pRb, p53, p16 and Cyclin D1 and Their Clinical Implications in Urothelial Carcinoma

The aim of this study was to assess immunohistochemical expression of p53, pRb, p16, and cyclin D1, alone or in combination, as prognostic indicators and to investigate their correlation with clinocopathologic features of urothelial carcinoma. Immunohistochemical staining for p53, pRb, p16, and cyclin D1 was performed on a tissue microarray from 103 patients with urothelial carcinoma who underwent radical cystectomy. Of the patient samples analyzed, 36 (35%), 61 (59%), 47 (46%) and 30 (29%) had altered expression of p53, pRb, p16, and cyclin D1, respectively. Abnormal expression of p53 and pRb correlated with depth of invasion (P=0.040 and P=0.044, respectively). Cyclin D1 expression was associated with tumor stage and recurrence (P=0.017 and P=0.036, respectively). Altered pRb was significantly correlated with overall survival (P=0.040). According to the expression pattern of pRb and p53, p53/pRb (altered/normal) had worse survival than p53/pRb (normal/altered) (P=0.022). Alteration of all markers had worse survival than all normal (P=0.029). As determined by multivariate analysis, tumor stage, lymph node metastasis and the combined expression of p53 and pRb are independent prognostic factors. In conclusion, immunohistochemical evaluation of cell cycle regulators, especially the p53/pRb combination, might be useful in planning appropriate treatment strategies.

Subclinical Cushing’s syndrome associated with an adrenocortical oncocytoma

Oncocytoma is a neoplasm that can arise in several organs, and it has been more commonly described in the kidney, salivary gland and thyroid. Oncocytoma arising in the adrenal gland is a rare finding. Moreover, functioning adrenocortical oncocytoma is exceptionally rare. A 47-yr-old man was incidentally discovered to have a right adrenal mass. The patient had no clinical features suggestive of increased adrenal function. However, hormonal evaluation showed a disturbed cortisol circadian rhythm, supranormal urinary cortisol excretion, a low level of ACTH, and a lack of suppressibility of cortisol secretion after dexamethasone. Right adrenalectomy was performed, and this revealed a well-circumscribed dark-brown tumor that measured 2.4x2.2 cm. The tumor consisted almost exclusively of large eosinophilic and epitheloid cells whose cytoplasm was packed with eosinophilic granulations, which corresponded to the numerous mitochondria confirmed on electron microscopy. This is a rare case of subclinical Cushing’s syndrome that was caused by adrenocortical oncocytoma.

Prognostic role of integrin β1, E‐cadherin, and rac1 expression in small cell lung cancer

Chang MH, Lee K, Lee K‐Y, Kim YS, Kim YK, Kang J‐H. Prognostic role of integrin β1, E‐cadherin, and rac1 expression in small cell lung cancer. APMIS 2012; 120: 28–38.

Relationship between circulating cytokine levels and thyroid function following bone marrow transplantation.

Summary:The relation between thyroid hormone changes and cytokines in bone marrow transplantation (BMT) patients has not been studied. This prospective study was designed to determine the relation between thyroid hormones and cytokine levels after BMT and their effects on the mortality. We studied 80 patients undergoing allogeneic BMT. Serum thyroid hormone parameters and cytokine levels were measured before and serially during 6 months after BMT. Serum T3 decreased to a nadir 3 weeks post-BMT and serum T4 was lowest at 3 months post-BMT. Serum thyroid stimulating hormone (TSH) sharply decreased to a nadir at 1 week and recovered. Serum interleukin-6 increased for 2 weeks after BMT and declined thereafter. Serum tumor necrosis factor-α increased for 3 weeks after BMT and declined thereafter. After 3 weeks post-BMT, both cytokine levels were negatively correlated with serum T3 and T4 levels. A total of 29 patients died before 1 year post-BMT and 51 patients survived longer than 1 year. Those patients who died before 1 year post-BMT had significantly lower levels of T4 at 3 weeks, 3 and 6 months than surviving patients. In conclusion, increased levels of serum IL-6 and TNF-α were negatively correlated with thyroid hormone concentrations in BMT recipients suggesting the role of these cytokines in euthyroid sick syndrome.