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.

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.

Eculizumab therapy in a patient with dense-deposit disease associated with partial lipodystropy.

BACKGROUND: Dense deposit disease (DDD) (also known as membranoproliferative glomerulonephritis type II) in childhood is a rare glomerulonephritis with frequent progression to end-stage renal disease (ESRD) and a high recurrence after kidney transplantation. The pathophysiologic basis of DDD is associated with the uncontrolled systemic activation of the alternative pathway (AP) of the complement cascade. CASE-DIAGNOSIS/TREATMENT: A 14-year-old girl presented with edema and nephrotic range proteinuria. Blood tests showed hypoalbuminemia, nephrotic range proteinuria, normal renal function, and a low C3 level. Renal biopsy confirmed the diagnosis of crescentic DDD. Complement analysis revealed strong AP activation (low C3), positive C3 nephritic factor (C3NeF), and a decreased complement factor H (CFH) levels with CFH polymorphisms. Therapy with eculizumab was considered after the failure of corticosteroid and plasmapheresis to modulate the ongoing massive proteinuria and persistence of low serum C3 levels. There was a marked clinical and biochemical response following the administration of eculizumab. CONCLUSIONS: Our case emphasizes the efficacy of eculizumab in the management of crescentic DDD in a patient with a normal renal function, in a short follow-up period. Considering previously reported cases, it appears that eculizumab represents a promising new approach which may prevent progression to ESRD in a subset of patients with DDD.

Unmasking the Silent Threat: COVID-19's Pervasive Impact on Renal Allografts.

OBJECTIVES: Growing evidence has highlighted the substantial effects of COVID-19 on kidneys, ranging from mild proteinuria to severe acute kidney injury. However, comprehensive assessments of histopathological features in renal allograft biopsies are lacking. MATERIALS AND METHODS: Seventeen kidney transplant recipients with COVID-19 between March 2020 and November 2022 were evaluated. Clinical characteristics, pathological findings, and outcomes were studied. RESULTS: Six kidney transplant recipients (35.3%) developed acute kidney injury, leading to the requirement for hemodialysis. COVID-19 severity, as indicated by pneumonia (P = .028) and hospitalization (P = .002), was significantly associated with development of acute kidney injury. Most patients with COVID-19 (82.4%) showed considerably increased proteinuria levels (82.4%), along with presence of new-onset microscopic hematuria (35.3%) and nephrotic syndrome (58.8%). Tubular viral inclusionlike changes were detected in 47.1% of cases and were associated with a higher risk of graft loss (75%). Thrombotic microangiopathy and endothelial cell swelling in glomeruli were prevalent, highlighting extensive endothelial cell injury. Most recipients (88.2%) experienced rejection after COVID-19, with graft loss occurring in 46.7% of these cases. Biopsies revealed collapsing (n = 5), noncollapsing (n = 3), and recurrent (n = 2) focal segmental glomerulosclerosis, as well as acute tubulointerstitial nephritis (n = 3), crescentic glomerulonephritis with immunoglobulin A nephropathy (n = 1), and membranoproliferative glomerulonephritis (n = 1), in 129.7 ± 33 days. Eight patients experienced graft loss (8.2 ± 2 mo posttransplant). Hospitalization (P = .044) and viralinclusion-like nuclear changes in tubules (P = .044) significantly influenced graft survival. Collapsing (60%) and noncollapsing (66.7%) focal segmental glomerulosclerosis increased the risk of graft loss. CONCLUSIONS: COVID-19 has had a multifaceted and enduring effect on renal allografts, urging the need for meticulous monitoring and tailored management strategies to mitigate the risk of severe kidney-related complications and graft loss in this vulnerable population.

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.

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.

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.

Protective role of simvastatin on lung damage caused by burn and cotton smoke inhalation in rats.

BACKGROUND: Smoke inhalation injury is a major comorbid factor in patients with thermal injury and occurs in about 30% of patients with major burns. In addition, inhalation injury reportedly accounts for 20%-84% of the mortality in burned individuals and is associated with higher mortality rates for every age and burn size category. The aim of the present study was to investigate the effects of simvastatin on lung damage with burn and cotton smoke inhalation. METHODS: Wistar rats were randomly assigned to three groups: saline treated control group, via an orogastric route (group 1, n = 6), burn (30%) and cotton smoke inhalated group (group 2, n = 6), and simvastatin treated (25 mg/kg/d, via an orogastric route) burn (30%) and cotton smoke inhalated group (group 3, n = 6). Rats were sacrificed at 48 h of the treatments and the trachea and lungs were removed completely. Tissue samples were taken for histopathologic, immunohistopathologic, and biochemical analyses. Univariate analysis of variance coupled with Duncan's post-hoc test was performed for statistical evaluation. RESULTS: Lung parenchymal and tracheoepithelial damage was confirmed in group 2 by histopathologic examination. Lung malonedialdehyde (MDA) levels were significantly decreased (P < 0.001), while glutathione (GSH) concentration did not alter in group 2 compared with group 1. Also, immunopathologic data revealed that epithelial iNOS level was elevated, while no modulation was detected in the level of myeloperoxidase (MPO). Simvastatin administration resulted in decreasing the lung parenchymal and tracheoepithelial damage. Tissue MDA levels were decreased significantly (P < 0.001), whereas GSH concentrations were elevated in group 3 compared with group 1 and group 2 (P < 0.001). Simvastatin treatment caused a decrease in epithelial iNOS levels, while MPO levels were not modulated. In addition, simvastatin significantly reduced pulmonary apoptosis in lung injury. CONCLUSIONS: Our results have indicated that simvastatin administration seems to play beneficial role in lung injury of rats promoted by combined burn and smoke inhalation. Thus, simvastatin may represent a potential approach to prevent smoke inhalation-associated lung dysfunction. However, the significant decrease in basal oxidant production may cause impairment in cellular signalling processes.

Early implant survival in posterior maxilla with or without beta-tricalcium phosphate sinus floor graft.

PURPOSE: The sinus lift procedure provides a way to increase the amount of available bone and the placement of longer implants. The aim of this study was to evaluate and compare the survival rates of implants inserted in the posterior maxilla (without sinus lift) to simultaneous implant insertion with sinus lift. PATIENTS AND METHODS: Seventy maxillary sinuses in 62 patients were augmented by beta-tricalcium phosphate and 121 implants were inserted into these augmented sinuses (study group) and 136 implants were inserted in the posterior maxilla in 65 patients (control group). Follow-up times were 29.8 and 32.3 months for the study and control groups, respectively. RESULTS: One implant in the study group and 1 implant in the control group failed. All other implants in both groups were functioning well without any significant clinical finding. Implant survivals were 99.17% in the study group and 99.26% in the control group. CONCLUSION: Simultaneous implant insertion and sinus lift with beta-tricalcium phosphate is a safe surgical procedure, and survival rates of implants inserted in the augmented sinus were similar to those of implants inserted in the posterior maxilla without sinus lift.

Clinical importance of vitamin D receptor gene polymorphism in invasive ductal carcinoma.

In this study, we aimed to investigate the clinical importance of the vitamin D receptor gene polymorphism in invasive ductal breast cancer. All patients included in the study had clinical T1-2, N0-M0 invasive ductal carcinoma. Patients' demographics, axillary metastasis status, metastatic lymph nodi/total dissected lymph nodes from axilla, histopathologic characteristics of tumors, local recurrences, and survival ratio were assessed. Vitamin D receptor B genotype frequencies in the patient group (P > 0.05) were as follows: B/b, 43 (77%); B/B, 13 (23%). In conclusion, the vitamin D receptor gene B allele does not seem to be related to local recurrence and distant metastasis of invasive ductal cancer of the breast.

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.

Apoptosis and expression of caspase-3 in cyclosporin-induced gingival overgrowth.

BACKGROUND: The pathogenesis of epithelial thickening in gingival overgrowth remains obscure. Apoptosis plays an important role in maintaining tissue hemostasis. The aim of the present study was to investigate apoptosis via immunohistochemical analyses in cyclosporin A-induced gingival overgrowth tissue samples to determine whether these processes play a role in the pathogenesis of gingival overgrowth. METHODS: Gingival biopsies (one per person) were harvested from 22 renal transplant recipients (eight men and 14 women; mean age, 36.4 +/- 13.3 years) who had been diagnosed with cyclosporin A-induced gingival enlargement and from 12 systemically healthy persons (seven men and five women; mean age, 27.0 +/- 16.0 years) with plaque-induced gingivitis. Distributions of caspase-3 and apoptosis were determined immunologically. RESULTS: Significant differences were found with regard to caspase-3 levels and the extent of apoptosis between the cyclosporin A group and the control group. Plaque index, gingival index, and probing depths were significantly lower in the control group. CONCLUSION: The extent of keratinocyte apoptosis and decreased levels of caspase-3 may be an important factor affecting the gingiva of kidney transplant recipients with cyclosporin A-induced gingival overgrowth.

Local and systemic interactions related to serum transforming growth factor-beta levels in burn wounds of various depths.

OBJECTIVES: This study aimed to investigate the interaction between serum levels of TGF-beta and active-immune cell infiltration in burn wounds of various depths. MATERIALS AND METHODS: Thirty female Sprague-Dawley rats were divided into three groups: full-thickness burns (F), partial-thickness burns (P), and no burns (S). After burn-induction, blood samples were obtained only once from shams and at postburn 1, 48 h, and 7 days in burn groups. Serum levels of TGF-beta were measured by means of the ELISA. The proportions of neutrophils, fibroblasts, vascular proliferation, CD68-macrophages, and CD3-lymphocytes were studied immunohistochemically and graded semiquantitatively. RESULTS: Serum TGF-beta levels in the F and P groups were lower than those in sham at 1h after burn (p<.05). No significant differences in TGF-beta were observed between groups F and P on days 2 and 7 after injury. No local accumulation of macrophages and fibroblasts was noted in either burn group, but the proportion of lymphocytes was higher in the P group at 1h after burn. Neutrophils were higher in the F group than the P on day 7 after burn. CONCLUSIONS: Prolonged neutrophil infiltration in full-thickness burn wounds and suppressed lymphocyte proliferation in partial-thickness burn wounds seem to be related to an increase in serum TGF-beta levels.

[Non-Hodgkin's lymphoma of the parotid gland]. / Parotis bezi non-Hodgkin lenfomasi

Most of the primary malignant lymphomas of the salivary glands originate from the parotid gland. We presented two patients who were admitted with a painless mass in the parotid region and diagnosed to have a lymphoma. Physical examination of a 66-year-old male patient showed a relatively mobile, painless, and firm mass at the inferior aspect of the right parotid gland. Ultrasonography, computed tomography, and magnetic resonance imaging (MRI) were performed and a needle biopsy was obtained from the solid lesion extending from the right parotid superficial lobe to the medial deep lobe. Pathological examination revealed large B-cell lymphoma. The patient was treated according to the CHOP chemotherapy protocol. The second patient had undergone surgery for orbital lymphoma and received CHOP chemotherapy. On physical examination, there was a painless mass in the parotid cauda on the left and a subcutaneous lymph node, 0.5 x 1 cm in size, inferior to the parotid cauda. Computed tomography and MRI showed an irregularly contoured solid lesion, 2 x 1 cm in size, in the posteroinferior aspect of the superficial lobe. Lymph node biopsy yielded a diagnosis of small cell malignant lymphoma. The patient was referred to the medical oncology department for staging, further investigation, and planning of the treatment.