Importance of Follow-Up Biopsies in the Prediction of Renal Allograft Survival Following Polyomavirus-Associated Nephropathy.

OBJECTIVES: Allograft biopsy is the gold standard for diagnosing polyomavirus-associated nephropathy. We aimed to establish the effects of histopathologic findings proposed by the Banff Polyomavirus Working Group on graft outcome. We also aimed to understand the clinical importance of follow-up biopsies for patients with polyomavirus-associated nephropathy. MATERIALS AND METHODS: Our study included 22 patients with polyomavirus-associated nephropathy. All biopsies were classified according to the latest Banff Polyomavirus Working Group classification. Follow-up biopsies of all patients were evaluated in detail. RESULTS: The mean interval between polyomavirus-associated nephropathy and transplant was 10 ± 1.6 months. Of 22 patients, biopsy revealed stage 1 in 3 (13.6%), stage 2 in 17 (77.3%), and stage 3 in 2 patients (9.1%). Fourteen patients (63.6%) had polyomavirus viral load 3, 5 (22.7%) had polyomavirus viral load 2, and 3 had polyomavirus viral load 1. Among patients included in analyses, 18.2% had antibody-mediated rejection and 27.2% had T-cell-mediated rejection simultaneously with polyomavirus-associated nephropathy. Graft loss increased with increasing polyomavirus-associated nephropathy class and polyomavirus viral load (P = .015 and P = .002, respectively). The mean time of graft survival decreased with increasing degree of tubulitis, interstitial inflammation, plasma infiltration, and neutrophil infiltration. Patients with interstitial fibrosis, glomerular polyoma, and cortical plus medullar involvement showed earlier graft loss. Follow-up biopsies showed that diffuse interstitial fibrosis or persistent inflam-mation negatively influenced graft loss. CONCLUSIONS: The Banff Polyomavirus Working Group's schema significantly correlated with graft outcome. Early detection of polyomavirus-associated nephro-pathy and subsequent detection of persistent inflammation and interstitial fibrosis and tubular atrophy in follow-up biopsies and modification of immunosuppressive therapy can successfully prevent graft loss.

The prognostic significance of tumor budding and the expression of focal adhesion kinase and survivin in lung adenocarcinoma.

OBJECTIVES: Adenocarcinoma is the tumor group with the highest incidence among lung cancers with poor prognosis. Tumor budding (TB) is the migration of single tumor cells or small clusters of cells from the neoplastic epithelium to the invasive front of the tumor. Focal adhesion kinase (FAK) and survivin are considered as poor prognostic factors in several tumors. Hence, we investigated TB, FAK, and survivin expression in lung adenocarcinoma. METHODS: The study included 103 cases of lung adenocarcinoma in the resection materials. In tumoral tissues; TB was counted and scored in one high-power field (HPF), as low if <5 in 1 HPF and high if ≥5 in 1 HPF. FAK and survivin were studied immunohistochemically. RESULTS: The mean number of TB in 1 HPF is 3.96 ± 2.8. Low-grade TB was observed in 45 (43.7 %) and high-grade TB was observed in 58 (56.3 %) patients. There was a positive correlation between TB and pT stage (p = 0.017), clinical stage (p = 0.002), lymphovascular invasion (p = 0.001), and perineural invasion (p = 0.045). The 4-year survival rate in patients was 90 % in those with low-grade TB and 60 % in those with high-grade TB (p = 0.001). FAK and survivin expressions were significantly increased in tumors with high-grade TB (p < 0.05). CONCLUSION: A significant correlation was found between the grade of TB and pT stage, clinical stage, lymphovascular and perineural invasion in lung adenocarcinoma. TB can be considered as a histological parameter showing poor prognosis. It is thought that high expression of FAK and survivin also affect the prognosis in these patients by increasing TB.

Tumor Microenvironment: Necroptosis Switches the Subtype of Liver Cancer While Necrosis Promotes Tumor Recurrence and Progression.

Liver cancer is a heterogeneous group of solid tumors that include mainly epithelial tumors. As with other solid carcinomas, tumor development results from an accumulation of genetic and epigenetic alterations. Hepatocellular carcinoma and intrahepatic cholangiocarcinoma, derived from malignant transformation of hepatocytes and cholangiocytes, respectively, are 2 primary types of liver cancers. However, it has been shown that the same kind of cell can give rise to different types of cancer, depending on manner of cell death in the tumor microenvironment. In a recent animal study, hepatocytes gave rise to both hepatocellular carcinoma and intrahepatic cholangiocarcinoma. Oncogenically activated hepatocytes were shown to give rise to intrahepatic cholangiocarcinoma or hepatocellular carcinoma depending on cell death type of neighboring cells. Hepatocytes within the necroptotic microenvironment gave rise to intrahepatic cholangiocarcinoma; however, hepatocytes harboring the same oncogenic driver gave rise to hepatocellular carcinoma within the apoptotic microenvironment. The hepatic cytokine microenvironment structured by the necroptosis can also switch hepatocellular carcinoma to intrahepatic cholangiocarcinoma independently of the oncogenic drivers. Cell death by necrosis in damaged livers can also lead to development of carcinoma. Cancer cells are known to be resistant to apoptosis as a result of p53 mutation. Therefore, necrosis is the primary cell death pathway in cancer therapy. Necrosis is associated with high levels of angiogenesis, tumor-associated macrophages, and increased inflammation in the tumor microenvironment. Patients with hepatocellular carcinoma or intrahepatic cholangiocarcinoma characterized by necrosis and tumor-associated macrophages have reduced overall survival and recurrence-free survival. Cytotoxicity from anticancer therapy can also lead to accelerated necrosis. The content of cells undergoing necrosis triggers cytokine secretion, which designs cancer progression via inflammatory and noninflammatory pathways. Thus, the tumor microenvironment and manner of cell death (necrosis, apoptosis, or necroptosis) are crucial factors in the development of primary liver cancers and tumor progression.

How Exercise Affects the Development and Progression of Hepatocellular Carcinoma by Changing the Biomolecular Status of the Tumor Microenvironment.

A sedentary lifestyle contributes to the development of nonalcoholic fatty liver disease. This disease is associated with hepatocellular carcinoma, even in the absence of cirrhosis. Nonalcoholic steatohepatitis mouse models have shown the benefits of regular exercise on hepatocellular carcinoma development. These models showed that total tumor volume per liver and tumor cell proliferation were reduced by exercise. Exercise also decreased the Ki-67-positive hepatocytes and increased p53 activity in the liver. In addition, an increased expression of Bcl-xL and the striking upregulation of p27 related to p53 activity were found in the liver. These findings suggest that p53 activation and resultant p27 expression are possible pathways by which exercise decreases hepatocyte proliferation and the development of tumor growth. Exercise could counteract hepatocellular carcinoma progression by activating adenosine monophosphate-activated protein kinase and thereby impairing mTORC1 activity. Impaired mTORC1 activity results in inhibition of cell proliferation in response to growth factors. The tumor suppressor PTEN was identified as a target of exercise by presenting increased expression in tumors of exercised rats. Loss of PTEN is shown to result in cell proliferation, growth, and invasion; therefore, increased expression of PTEN in a tumor will abate the cell proliferation and tumor growth. In addition, STAT3, a downstream factor of the mechanistic target of rapamycin that plays a role in tumor angiogenesis and metastasis, has been shown to be decreased in exercised rats. Thus, prevention of its activation will inhibit growth of hepatocellular carcinoma. In clinical studies, exercise was positively associated with improved recurrence-free survival in patients with hepatocellular carcinoma. Exercise may slow cancer progression by direct action on tumor-intrinsic factors and signaling pathways, thus possibly improving the efficacy of the anticancer treatment. This review explains the potential anticancer benefits of exercise by highlighting the tumor-intrinsic factors and signaling pathways of hepatocellular carcinoma associated with exercise.

Association between focal adhesion kinase and matrix metalloproteinase-9 expression in prostate adenocarcinoma and their influence on the progression of prostatic adenocarcinoma.

Focal adhesion kinase (FAK), a member of the non-receptor cytoplasmic tyrosine kinase family, is associated with the development and progression of cancer. Matrix metalloproteinase-9 (MMP-9) is directly involved in the degradation of the extracellular matrix, and basement membrane components promote cancer cell migration and invasion. There is a functional interaction among FAK, MMP-9 and vascular endothelial growth factor (VEGF), which leads to enhanced cancer angiogenesis, cancer cell invasion and progression of malignancy. FAK, MMP-9, VEGF and CD34-positive microvessel density (MVD) were examined in 100 patients with prostate adenocarcinoma using immunohistochemistry. The relationship among these proteins and their impact on angiogenesis and clinicopathological parameters were also evaluated. The FAK expression was found to be positively correlated with the Gleason score, WHO grade group, tumour stage, extracapsular extension and perineural invasion. The MMP-9 expression was positively correlated with the WHO grade group, tumour stage, extracapsular extension, positive surgical margin and lymphovascular and perineural invasion. The FAK expression was also positively correlated with MMP-9 expression and MVD. However, no correlation between FAK and VEGF expression was identified. The MMP-9 expression was positively correlated with FAK expression and MVD. Strong MMP-9 expression was associated with shorter disease-free survival. These results suggest that strong MMP-9 and FAK expressions play an essential role in the progression of prostate adenocarcinoma. Further investigations should be conducted to determine the importance of these proteins as therapeutic targets for patients with prostate adenocarcinomas.

Evaluation of New Baskent University Preservation Solution for Kidney Graft During Cold Ischemia: Preliminary Experimental Animal Study.

OBJECTIVES: Organ damage due to long cold ischemia time remains a hurdle in transplantation. In this preliminary animal study, we compared the new Baskent University Preservation Solution (BUPS) with the University of Wisconsin (UW) and histidine-tryptophan-ketoglutarate (HTK) solutions. MATERIALS AND METHODS: BUPS composition included electrolytes, raffinose, mannitol, N-acetylcysteine, taurine, adenosine, and ascorbic acid. In experiment 1, kidneys from 50 male Sprague-Dawley rats were placed into BUPS, HTK, or UW solution to assess cold ischemia injury, with biopsies taken at different time points for pathologic evaluation. In experiment 2, to investigate ischemia-reperfusion injury, 5 rats were renal transplant donors to 10 rats and 6 pigs were used as transplant donors-recipients among each other. RESULTS: In experiment 1, no significant cellular injury was shown at up to 3 hours of perfusion with any solution. At 6- to 48-hour perfusion, tubular injury was shown, with lowest injury in BUPS and HTK versus UW and control groups (P < .01). The BUPS group showed more moderate degree of tubular apoptosis and cytoskeletal rearrangement than the HTK and UW groups at 12-, 24-, and 48-hour perfusion (P < .01). In experiment 2, after ischemia-reperfusion injury, no significant differences were found between HTK and BUPS groups regarding tubular damage. Although no significant differences were shown regarding tubular cytoskeletal rearrangment and apoptosis in pig reperfusion group with BUPS versus HTK, significant differences were shown with these solutions in other groups. CONCLUSIONS: Tubular damage during ischemia-reperfusion injury (cytoskeletal disruption, increased apoptosis) were lower with BUPS. BUPS can be a cost-effective perfusion solution in transplantation.

Gastrointestinal Stromal Tumors: A Clinicopathological and Immunohistochemical Study of 65 Cases.

OBJECTIVE: The clinical behavior of gastrointestinal stromal tumors is divergent. The aim of the present study was to define the clinicopathological features that determine the patient's outcome. MATERIAL AND METHOD: Sixty-five gastrointestinal stromal tumors were reviewed with their histological, immunohistochemical and clinical features and compared with their clinical outcome statistically. RESULTS: Tumors were located in the stomach (n=39, 60%), small intestine (n=22, 33.8%) and large intestine (n=4, 6.2%). Immunohistochemically, CD 117 positivity was found in 90.8%, whereas CD34, Smooth muscle actin, Desmin and S100 positivity was found in 73.3%, 61.7%, 11.7% and 28.3% of tumors respectively. All six ''CD 117-negative'' cases expressed DOG-1. The mean Ki-67 proliferation index was 8.69%±12.76. Liver metastasis was detected in seven cases. A significant association was detected between decreased mean survival time and increased tumor size (p < 0.001), large bowel localization (p=0.047), mitosis (p < 0.001), the presence of necrosis (p=0.001), metastasis (p=0.033), Ki-67 proliferation index (p=0.002) and risk category (p < 0.001). CD 34 positivity was mostly seen in the stomach (p=0.001), and CD 34 positive tumors had longer overall survival (92.85.±5.77 months versus 67.21±13.68 months) (p=0.046). Higher Ki-67 proliferation index (≥6%) was also correlated with the presence of metastases (p=0.015). CONCLUSION: Our study indicates that in addition to well-known risk factors such as increased tumor size, high mitotic activity and metastasis; higher Ki-67 proliferation index, the presence of necrosis, and CD34 negativity also correlate with shorter survival time.

Liver Biopsy Results in Potential Donor Evaluation in Living Related Liver Transplant.

OBJECTIVES: The number of living-donor liver transplants has been increasing due to the growing discrepancy between the number of patients on wait lists for liver transplant and the availability of deceased donations. Evaluations of potential liver donors should ensure the safety of the surgical procedure for both the donor and recipient. Liver biopsy is the criterion standard for selecting optimal donors. In this study, we evaluated the importance of preoperative liver biopsy in selecting donor candidates. MATERIALS AND METHODS: We evaluated the data of 612 living-related liver donor candidates who received liver biopsies between January 2001 and June 2017 at our center. RESULTS: In the 612 liver donor candidates (328 male, 284 female; age range, 18-69 years), 416 liver biopsies (68%) were reported as normal and 196 liver biopsies (32%) had pathologic findings. Of 196 donors with pathologic findings, 86 (44%) had fatty changes and 24 (12%) had portal inflammation. CONCLUSIONS: The high rate of pathologic findings in liver biopsy of healthy-appearing donor candidates indicated the importance of liver biopsy in the preoperative evaluation of donors.

Pretransplant Renal Arterial Vasculopathy of Donor Predicts Poor Renal Allograft Survival.

OBJECTIVES: Transplant vasculopathy is a significant predictor of poor outcome. We investigated whether age or pretransplant renal arterial vasculopathy of grafted kidneys affected allograft survival. MATERIALS AND METHODS: This study included 148 recipients and their donors. All donors underwent pretransplant renal arterial biopsy, with renal artery vascular score determined for each artery. Chronic rejection and graft loss were noted for all patients. RESULTS: Variable grades of pretransplant renal arterial lesions were noted in 103 donors (69.6%). A positive correlation was found between donor age and renal artery score (r = 0.650, P < .001), and chronic rejection and graft loss were found to increase with increasing score (P < .001). Recipient and donor age was significantly associated with graft loss and chronic rejection. With either younger or older donors, recipients had similar and best results regarding chronic rejection and graft loss if donors had renal artery scores of 0 or 1, but worse effects if donors had scores of 2 or 3. Five-year allograft survival rates for scores of 0, 1, 2, and 3 were 91%, 68%, 46%, and 33%. Univariate analyses showed that acute rejection episode (relative risk: 2.729, 95% confidence interval, 1.496-4.977; P = .001), older (? 50 y) donor age (relative risk: 1.970, 95% confidence interval, 1.038-3.736; P = .04), and donor renal artery score (relative risk: 2.466, 95% confidence interval, 1.382-4.401; P = .002) were associated with decreased allograft survival. Multivariate Cox analysis showed that only acute rejection episode (relative risk: 3.585, 95% confidence interval, 1.781-7.217; P < .001) and renal artery score (relative risk: 2.642; 95% confidence interval, 1.355-5.150; P = .004) were independent predictors of allograft survival. CONCLUSIONS: Pretransplant vasculopathy in donor renal artery implies a poor prognosis for renal allograft survival and is independent of other risk factors. Pretransplant renal artery biopsy is recommended for both deceased and living donors, and therapeutic interventions to modify transplant vasculopathy progression should start early posttransplant in recipients with affected renal arteries.

De Novo Thrombotic Microangiopathy in Renal Transplant Patients.

OBJECTIVES: Thrombotic microangiopathy is a form of renal capillary injury possibly associated with calcineurin inhibitor toxicity, acute humoral rejection, infections, and recurrent diseases. Here, we examined its incidence in patients diagnosed with acute and chronic active humoral rejection, polyomavirus nephropathy, acute cellular rejection, and immunoglobulin A recurrence. MATERIALS AND METHODS: In total, 272 renal allograft recipients who met the inclusion criteria were reevaluated for presence of renal thrombotic microangiopathy. Thrombotic microangiopathy diagnosis was established by clinical, laboratory, and histologic features. C4d expression in peritubular capillaries was determined. Clinical data were collected from medical records. RESULTS: Of 272 patients (mean age of 42.8 ± 12.7 years), only 74 patients (27.2%) had de novo thrombotic microangiopathy, which was found in 30/90 patients (33.3%) with acute humoral rejection, 9/51 (17.6%) with acute cellular rejection, 22/53 (41.5%) with chronic active humoral rejection, 10/55 (18.2%) with polyomavirus nephropathy, and 3/23 (13%) with immunoglobulin A nephropathy. Significant differences were shown between therapy type and thrombotic microangiopathy development (P = .02). Patients who received cyclosporine (38.5%) tended to show higher incidence of thrombotic microangiopathy than patients who received tacrolimus (20.7%) or sirolimus (7.7%). Patients with C4d-positive acute humoral (97.6% vs 2.4%) and chronic active humoral rejection (68.2% vs 31.8%) had greater incidence of thrombotic microangiopathy versus those who were C4d-negative. Graft loss was significantly higher in C4d-positive than in C4d-negative thrombotic microangiopathy groups (P < .001). Overall 1-, 3-, and 5-year graft survival was 94%, 85%, and 85% versus 83%, 51%, and 51% in thrombotic microangiopathy-negative versus thrombotic microangiopathy-positive patients (P < .001). CONCLUSIONS: Acute humoral rejection and chronic active humoral rejection were the most common and therefore most important causes of de novo thrombotic microangiopathy in renal transplant patients. Its presence in the renal allograft biopsy should arouse suspicion for underlying acute or chronic active humoral rejection.

Renal Allograft With Calcium Oxalate Deposition: Association with Urinary Tract Infection and Development of Interstitial Fibrosis.

OBJECTIVES: The interaction between calcium oxalate deposition and urinary tract infection is not well established. We aimed to identify the association between these and to determine the role of calcium oxalate deposition on interstitial fibrosis development. MATERIALS AND METHODS: Renal allograft biopsies of 967 patients were reviewed to identify those with calcium oxalate deposition in the renal allograft, with 27 (2.8%) identified. Follow-up biopsies were conducted to reevaluate for calcium oxalate presence and interstitial fibrosis development. At time of biopsy, presence of urinary tract infection and oxaluria was also examined from medical records. RESULTS: Mean time for development of calcium oxalate deposition in renal allografts was 1.7 ± 0.4 and 32.7 ± 21.6 months in patients with primary and secondary oxalosis, respectively (P < .001). Of 27 patients with calcium oxalate deposition, 7 (25.9%) showed tubulointerstitial nephritis, with 2 also having urinary tract infection. Four patients (14.8%) had only urinary tract infection. Causes of tubulointerstitial nephritis were secondary to bacterial infection in 2 and secondary to viral infection in 5 patients (2 polyomaviruses, 2 cytomegaloviruses, 1 adenovirus). Time until development of interstitial fibrosis after calcium oxalate deposition was 3.5 ± 2.1 and 10.3 ± 4.1 months in patients with primary and secondary oxalosis, respectively (P = .01). Time until graft loss after calcium oxalate deposition was 9.3 ± 7.8 and 21.8 ± 12 months in those with primary and secondary oxalosis (P < .001), with 1-, 3-, and 5-year kidney graft survival of 43%, 28%, and 0% and 100%, 100%, and 67% in those with primary and secondary oxalosis, respectively. CONCLUSIONS: Calcium oxalate deposits increased the risk of urinary tract infection and tubulointerstitial nephritis, with bacteria inducing increased presence of calcium oxalate deposition in a renal allograft. Calcium oxalate deposition had a significant influence on interstitial fibrosis development, therefore negatively affecting graft survival.

Posttransplant Lymphoproliferative Disorder Manifesting as Intestinal Epstein-Barr Virus-Positive Anaplastic Large-Cell Lymphoma in an Adult Renal Transplant Recipient.

Posttransplant lymphoproliferative disorder is a relatively common posttransplant malignancy affecting as many as 10% of all solid-organ recipients. Most cases of posttransplant lymphoproliferative disorder are of B-cell origin, with common Epstein-Barr virus association. Posttransplant lymphoproliferative disorders of T-cell origin are much rarer and less frequently associated with Epstein-Barr virus. Here, we report an unusual case of Epstein-Barr virus-positive anaplastic large-cell lymphoma causing an intestinal perforation in an adult renal transplant recipient. A 52-year-old male patient with renal allograft developed cryptogenic end-stage liver failure and was accepted as a candidate for liver transplant. Before transplant, he was admitted with severe abdominal pain, which turned out to result from ileal perforation. Pathologic evaluation of the intestinal resection showed diffuse malignant lymphoid infiltration of the ileum, consistent with anaplastic large-cell lymphoma. The tumor was positive for Epstein-Barr virus genome. Anaplastic large-cell lymphoma is a rare form of T-cell posttransplant lymphoproliferative disorder that is infrequently associated with Epstein-Barr virus. The occurrence of this extraordinary form of post transplant lymphoproliferative disorder, its late onset, intestinal localization, and Epstein-Barr virus as sociation represent a unique clinical rarity.

Splenic Peliosis Resulting in Spontaneous Splenic Rupture in a Concomitant Hepatic and Renal Allograft Recipient.

Splenic peliosis is an exceedingly rare complication following liver and kidney transplant, with few previously reported cases. A 24-year-old man with chronic renal and hepatic failure due to primary oxalosis underwent concomitant renal and hepatic transplant. On the eighth day of successful transplant, he showed signs and symptoms of hypovolemia with suspicion of intra-abdominal bleeding. Diagnostic laparotomy was performed, yielding splenic rupture, and a splenectomy was performed. Macroscopically, the spleen was ruptured, and the cut surface displayed multiple parenchymal blood-filled cysts. Microscopically, the splenic microarchitecture was distorted by numerous irregular hemorrhagic lacunes partially lined by sinusoidal endothelium. Splenic peliosis was diagnosed. The patient recovered with splenectomy. Peliosis is a condition characterized by multiple bloodfilled cavities in parenchymatous organs, and it most frequently affects the liver. It is thought to be related to many conditions, including hematologic malignancies, acquired immuno deficiency syndrome, chronic alcoholism, use of oral contraceptives, and posttransplant immunodeficiency state. However, peliosis of the spleen, compared with the liver, is relatively rare, and it may cause spontaneous splenic rupture. Although rare, splenic peliosis and secondary splenic rupture is a significant posttransplant complications leading to unexplained hypovolemia.

Role of tumor-associated macrophages in the Hexim1 and TGFß/SMAD pathway, and their influence on progression of prostatic adenocarcinoma.

BACKGROUND: Hexamethylene bisacetamide-inducible protein 1 (Hexim1) regulates transforming growth factor-ß (TGFß) activity and turnover of SMAD proteins in a cyclin-dependent kinase 9-dependent way. It does so specifically through inhibiting function of this enzyme and by inhibiting the transcriptional activity of positive transcription elongation factor b (P-TEFb). Tumor-associated macrophages (TAMs) play a role in the progression of prostate adenocarcinomas. We investigated the clinicopathological significance of Hexim1, TGFß, SMAD2, and SMAD7 expression in prostate adenocarcinoma cells, and assessed associations between TAMs density and these proteins. METHODS: The cases of 100 patients diagnosed with prostate acinar adenocarcinoma who had undergone radical prostatectomy were retrospectively examined. Each was reviewed for Gleason score, cancer stage, and specific histopathological features. Original slides were re-examined, and new slides were prepared and immunostained with Hexim1, TGFß, SMAD2, SMAD7 and CD68. RESULTS: Hexim1 expression was positively correlated with Gleason score, cancer stage, lymphovascular invasion, perineural invasion, extracapsular extension, and positive surgical margin. TAMs density was positively correlated with Gleason score, cancer stage, perineural invasion, extracapsular extension, and positive surgical margin. TAMs density was positively correlated with Hexim1 expression and TGFß expression. More advanced cancer stage, lymphovascular invasion, perineural invasion, and extracapsular extension were correlated with strong Hexim1 expression, strong SMAD2 expression, and mild SMAD7 expression, respectively. Strong Hexim1 expression, strong TGFß expression, and mild SMAD7 expression were associated with higher Gleason score. Strong Hexim1 expression was correlated with strong TGFß expression and mild SMAD7 expression. Strong Hexim1 expression, strong SMAD2 expression, and mild expression of SMAD7 were associated with disease progression. Strong SMAD2 expression was associated with shorter disease-free survival. CONCLUSION: The results suggest that greater TAMs density, strong Hexim1 expression, strong SMAD2 expression, and mild SMAD7 expression play important roles in the progression of prostate adenocarcinoma. Further investigation of these proteins will help facilitate the definitive prognosis of prostate adenocarcinomas. Ultimately, these proteins may be therapeutic targets for patients with prostate cancer.

The Effect of Hepatitis B Virus on Graft and Overall Survival in Kidney Transplant Patients.

OBJECTIVES: We investigated the effect of hepatitis B virus in kidney transplant patients in terms of patient care and survival. MATERIALS AND METHODS: We retrospectively analyzed kidney transplant patients from 1993 to 2013. A control group with negative serology was selected. The hepatitis B virus-positive group was divided into 2 subgroups based on serologic status, treatments, and treatment responses. Group A had viral suppression, and group B had hepatitis B virus DNA persistence. Overall and allograft survival rates were compared. RESULTS: We identified 32 hepatitis B virus-positive and 74 hepatitis B virus-negative patients. Positive group was treated with lamivudine (n = 23), lamivudine plus entecavir (n = 4), lamivudine plus tenofovir (n = 4), or lamivudine plus entecavir and tenofovir (n = 1). In group A (n = 15), antiviral treatment was given based on the presence of either hepatitis B surface antigen with negative hepatitis B virus DNA (n = 11) or hepatitis B virus DNA positivity (n = 4). Group B patients (n = 17) received antiviral treatment for persistence of hepatitis B virus DNA (n = 7) or for viral reactivation (ie, recurrence of hepatitis B virus DNA) (n = 10). Groups A and B did not differ significantly in terms of graft or overall survival. Liver biopsy was performed in 17 patients; 3 patients had high-grade fibrosis or cirrhosis, and 14 patients had normal histology or mild hepatitis. Median graft survival time was longer in positive group (69.5 mo vs 54 mo; P = .007). Five- and 10-year overall survival rates were comparable (89%-84% vs 96%-96%; P = .107). CONCLUSIONS: Hepatitis B virus-positive kidney transplant patients have increased liver transaminase levels, longer graft survival times, and similar median overall survival rates compared with hepatitis B virus-negative patients.

Late-Onset Drug-Induced Cholestasis in a Living-Related Liver Transplant Donor With Progressive Familial Intrahepatic Cholestasis.

We present a rare case of progressive familial intrahepatic cholestasis within a family. A 34-yearold female became a living-related liver transplant donor for her son, who had the disease. Nine years after the transplant, the mother developed severe intrahepatic cholestasis, for which she was evaluated after using an oral contraceptive drug. She presented with jaundice, pruritus, and increased bilirubin levels, together with elevated gamma glutamyl transferase and alkaline phosphatase levels. A liver biopsy revealed findings consistent with intrahepatic cholestasis. However, despite follow-up management and cessation of the insulting drug, her total bilirubin count continuously increased to 20 mg/dL and was accompanied by intractable pruritus. A total of 9 plasmapheresis sessions were performed, and she was started on a regimen of ursodeoxycholic acid (13 mg/kg/d) and cholestyramine (4 g, 3 times daily). The clinical and laboratory picture dramatically improved following cessation of the oral contraceptive, plasmapheresis sessions, and drug treatment. The patient's cholestasis normalized within 3 months, and she recovered uneventfully. A genetic analysis of the whole family revealed that both parents were heterozygous for the mutation c.124G>A in ABCB11, and the son was homozygous for this mutation. These findings supported varying degrees of bile salt export pump deficiency in the family members. Defective bile salt excretory system function can result in a wide spectrum of clinical presentations, ranging from progressive familial intrahepatic cholestasis requiring liver transplant to late-onset drug-induced cholestasis. Our findings suggest that, in a heterozygous carrier of a progressive familial intrahepatic cholestasis mutation, drug-induced cholestasis is responsive to treatment, after which the clinical picture can normalize within 3 months.

Effect of pentoxifylline on healing of segmental bone defects and angiogenesis.

OBJECTIVE: The aim of this study was to determine the effect of pentoxifylline (PTX) on angiogenesis and the healing of a critical-sized segmental defect of the radius diaphysis in a rat model, using radiological and histological grading systems. METHODS: The study included 24 female Sprague-Dawley rats (weight: 300±20 g) divided into 4 groups. A critical-sized segmental defect was created in the radius diaphysis in all rats. In Group 1, morcellized iliac crest autografts were used to fill the segmental bone defect. In Group 2, segmental bone defects were filled using morcellized iliac crest autografts, and 25 mg/kg/day PTX was applied intraperitoneally. In Group 3, the segmental bone defects were not filled, and in Group 4 the segmental bone defects were left unfilled, and an intraperitoneal (IP) dose of 25 mg/kg/day PTX was applied. Rats were sacrificed at postoperative Week 8, and defects were evaluated using radiographic, histological and immunohistochemical methods. RESULTS: There were significant differences between Group 1 and 2 according to radiological evaluation (p=0.003) and quality of union at the defect site (p=0.01). Union quality was higher in Group 4 than Group 3 (p=0.01). Cluster of differentiation 31 (CD31) and vascular endothelial growth factor (VEGF) levels were higher in Group 2 than in Groups 3 and 4. CONCLUSION: According to radiological and histological parameters, PTX appears to improve angiogenesis and healing of segmental cortical bone defects of the radius in a rat model.

Bone marrow biopsy in patients with renal transplant: spectrum of findings and diagnostic use.

OBJECTIVES: Renal transplant may be complicated by cytopenia, fever of unknown etiology, or hematolymphoid malignancies. Bone marrow biopsy may be indicated to evaluate these complications. However, to the best of our knowledge, no previous study has systematically documented the characteristics of bone marrow biopsy in these patients. The present study reports the range of bone marrow findings in renal transplant recipients. MATERIALS AND METHODS: We selected 85 patients who underwent bone marrow biopsy among 1745 renal transplant recipients who had transplant at Ba skent University from January 1990 to December 2013. The files of these patients were reviewed for age, sex, age at renal transplant, underlying renal disease, donor type, immunosuppressive therapy, presence or absence of acute humoral or cellular rejection, duration between transplant and bone marrow biopsy, indication for bone marrow biopsy, and histopathologic diagnoses of bone marrow biopsies. RESULTS: The most common cause of renal insufficiency leading to transplant in this patient group was unknown etiology, observed in 24 patients (28.2%). The most common indication for bone marrow biopsy was blood cytopenia, detected in 56 patients (65.9%). Neoplastic involvement of the bone marrow was detected in 6 patients (7.1%), all of which were hematolymphoid malignancies. Corticosteroids were the most commonly used immunosuppressive agents, administered to all patients. CONCLUSIONS: Bone marrow biopsy provides important information in renal transplant recipients, especially in cases of neoplastic bone marrow involvement, specific inflammation, and amyloidosis, which are uncommon in this patient group. The overall diagnostic use is related to the individual situation of each patient.

Role of bronchoalveolar lavage in diagnosis of fungal infections in liver transplant recipients.

OBJECTIVES: Pulmonary fungal infections remain the most important cause of morbidity and mortality in liver transplant recipients. Fast and accurate causative diagnoses are essential for a good outcome. Bronchoscopy with bronchoalveolar lavage frequently is performed to diagnose pulmonary infections in immunocompromised patients. The aim of this study was to evaluate the diagnostic use of bronchoalveolar lavage in liver transplant recipients with pulmonary infections. MATERIALS AND METHODS: We retrospectively analyzed the data of 408 patients who underwent liver transplant from January 1990 to December 2012. Patients who underwent bronchoalveolar lavage after transplant were included in this study. RESULTS: There were 18 of 408 liver transplant recipients (4.41%) who underwent bronchoalveolar lavage after transplant. The mean age was 49.5 ± 18 years. In 5 patients (27.8%), fungal microorganisms were observed in the cytology of bronchoalveolar lavage specimens, including Aspergillus fumigatus in 3 patients and Candida albicans in 2 patients. Death occurred in 4 of 5 patients (80%) with fungal infections. No association was observed between the presence of fungal infection and clinical and radiographic findings of the patients. CONCLUSIONS: Bronchoscopy with bronchoalveolar lavage is a useful, noninvasive diagnostic tool for the rapid diagnosis of infections in solid-organ transplant recipients.

Spectrum of histopathologic diagnosis of lymph node biopsies after liver and kidney transplant.

OBJECTIVES: Our aim was to review our single center experience regarding histopathologic features arising from enlarged lymph nodes following solidorgan transplant. MATERIALS AND METHODS: In 2148 people who had solid-organ transplant from 1985 to 2013, there were 34 patients (1.58%) who developed lymphadenopathy. A retrospective review was performed to evaluate demographic, clinical, and histopathologic features of medical and pathologic records. RESULTS: Nonneoplastic lesions were more common, comprising 70.5% (n = 24) all cases which included nonspecific reactive lymphoid hyperplasia in 8 patients (33.3%), tuberculous lymphadenitis in 6 patients (25%), amyloid lymphadenopathy in 4 patients (16.6%), dermatopathic lymphadenopathy in 2 patients (8.3%), Kikuchi-Fujimoto disease in 1 patient (4.16%), hemangioma in 1 patient (4.16%), plasmacytic form of Castleman disease and amyloid lymphadenopathy in 1 patient (4.16%), and sea blue histiocytosis in 1 patient (4.16%). Neoplastic lesions comprised 29.41% (n = 10) cases which included posttransplant lymphoproliferative disorder in 6 patients (60%), Kaposi sarcoma in 2 patients (20%), posttransplant lymphoproliferative disorder and Kaposi sarcoma in 1 patient (10%), and metastatic carcinoma in 1 patient (10%). CONCLUSIONS: Detecting enlarged lymph nodes in solid-organ transplant recipients is an infrequent occurrence. Infectious diseases, posttransplant lymphoproliferative disorder, and malignancies related to transplant should be considered in the differential diagnosis when enlarged lymph nodes in solid-organ transplant recipients are encountered.