Differences In Histopathological Features Research Articles

Histopathologic Features and Transcriptomic Signatures Do Not Solve the Issue of Magnetic Resonance Imaging-Invisible Prostate Cancers: A Matched-Pair Analysis.

Multiparametric magnetic resonance imaging (mpMRI) is pivotal in prostate cancer (PCa) diagnosis, but some clinically significant (cs) PCa remain undetected. This study aims to understand the pathological and molecular basis for csPCa visibility at mpMRI. We performed a retrospective matched-pair cohort study, including patients undergoing radical prostatectomy (RP) for csPCa (i.e., ISUP grade group ≥ 2) from 2015 to 2020, in our tertiary-referral center. We screened for inclusion in the "mpMRI-invisible" cohort all consecutive men (N = 45) having a negative preoperative mpMRI. The "mpMRI-visible" cohort was matched based on age, PSA, prostate volume, ISUP grade group. Included patients underwent radiological and pathological open-label revisions and characterization of the tumor mRNA expression profile (analyzing 780 gene transcripts, signaling pathways, and cell-type profiling). We compared the clinical-pathological variables and the gene expression profile between matched pairs. The analysis was stratified according to histological characteristics and lesion diameter. We included 34 patients (17 per cohort); mean age at RP and PSA were 70.5 years (standard deviation [SD] = 7.7), 7.1 ng/mL (SD = 3.3), respectively; 65% of men were ISUP 2. Overall, no significant differences in histopathological features, tumor diameter and location, mRNA profile, pathways, and cell-type scores emerged between cohorts. In the stratified analysis, an upregulation of cell adhesion and motility, of extracellular matrix remodeling and of metastatic process pathways was present in specific subgroups of mpMRI-invisible cancers. No PCa pathological or gene-expression hallmarks explaining mp-MRI invisibility were identified. Aggressive features can be present both in mpMRI-invisible and -visible tumors.

Unravelling switch/sucrose non-fermentable (SWI-SNF) complex-deficient thoracic tumours: a clinicopathological comparative on undifferentiated tumours and non-small cell lung carcinomas with BRG1 and BRM deficiency

AimsThis study was undertaken to compare and expand the clinicopathological characteristics of SMARCA4-deficient thoracic undifferentiated tumour (SMARCA4-dUT) and switch/sucrose non-fermentable-deficient non-small cell lung carcinomas (SWI/SNF-dNSCLC) and to address cases with...

Penile cancer in younger men-A more aggressive disease?

Penile cancer (PC) in men under 45 is very rare with an incidence of 0.1 to 0.8/100,000. There is little published data on disease characteristics and outcomes of PC in younger men. Herein, we evaluate the disease characteristics and outcomes of penile cancer in younger men compared to an older cohort. This study included all men diagnosed with PC at our institution from 2016 to 2021. Primary outcomes included overall survival, cancer-specific survival, and disease-free survival. Secondary outcomes included disease characteristics and surgical management. Men aged ≤45 years (Group A) were compared with men aged >45 years (Group B) at diagnosis. There were 90 patients treated for invasive PC over the study period. The median age at diagnosis was 64 (26-88). The mean length of follow-up was 27 (±18) months. There were 12 (13%) in Group A, and 78 (87%) patients in Group B. Group A had a worse cancer-specific survival compared to Group B (39 months vs. not reached, HR 0.1 (95%CI 0.02-0.85, P = 0.03). There was no significant difference in overall or disease-free survival between both groups. More men in Group A had lymph node metastases at the time of diagnosis (58% vs. 19%, P < 0.001). There was no significant difference in histopathological features including tumor subtype, grade, T stage, p53 status or presence of lymphovascular or perineural invasion. In our study, younger men were more likely to have nodal involvement at time of diagnosis and had a worse cancer-specific survival.

The Effect of Risk-Reducing Salpingo-Oophorectomy on Breast Cancer Incidence and Histopathological Features in Women with a BRCA1 or BRCA2 Germline Pathogenic Variant

Risk-reducing salpingo-oophorectomy (RRSO) is advised for female BRCA1/2 germline pathogenic variant (GPV) carriers to reduce tubal/ovarian cancer risk. RRSO may also affect breast cancer (BC) incidence. The aim was to investigate the effect of RRSO on BC incidence and histopathological features in female BRCA1/2 GPV carriers. Prospectively collected clinical data from BRCA1/2 GPV carriers in our hospital-based data/biobank were linked to the Dutch Nationwide Pathology Databank (PALGA) in January 2022. Multivariable Cox-proportional hazard models were used to calculate hazard ratios (HRs) with 95% confidence intervals (95% CIs), where the pre-RRSO group was considered the reference group and the primary endpoint was the first primary BC. Histopathological features of BCs pre- and post-RRSO were compared using descriptive statistics. In 1312 women, 164 incident primary BCs were observed. RRSO did not decrease BC risk for BRCA1 GPV (HR: 1.48, 95% CI: 0.91-2.39) or BRCA2 GPV (HR: 0.95, 95% CI: 0.43-2.07) carriers. BCs tended to be smaller post-RRSO (median: 12 mm) than pre-RRSO (15 mm, p: 0.08). There were no statistically significant differences in histopathological features. RRSO did not decrease BC risk or affect BC features in BRCA1/2 GPV in this study, although BCs diagnosed post-RRSO tended to be smaller.

Immunohistochemical differential expression of p16 proteins in follicular type and plexiform type ameloblastoma

Background: Differences in histopathological features that describe the growth mechanism and biological behaviour of follicular and plexiform ameloblastomas are associated with benign, aggressive and destructive tumour markers. p16 has inhibitory interactions between cyclin D and CDK 4/6 to block the cell cycle and alterations related to severity. Purpose: This study intends to evaluate and determine differential expressions of p16 protein in follicular and plexiform ameloblastomas. Methods: This is a descriptive analytics study. A total of 21 specimens consisting of follicular and plexiform ameloblastomas and healthy gingiva tissues as the negative control were examined using the immunohistochemistry assay. The analysis of p16 protein expression was interpreted by immunoreactive scoring. Statistical analysis was conducted using SPSS software with the Mann–Whitney test. A p-value &lt;0.05 shows the significance of the change in expression. Results: An increased expression of p16 protein was found in the follicular ameloblastoma type (2.13 ± 1.808) and the plexiform type (4.44 ± 2.506) in comparison to the negative control group (0 ± 0). The increase of p16 expression in the follicular and plexiform ameloblastomas was significant compared to the negative control group (p-value &lt;0.05); however, there was no significant difference between either type of ameloblastoma (p-value &gt;0.05). Conclusion: The highest intensity of p16 protein expression was found in the plexiform type, even though it was not significantly different from the follicular type ameloblastoma.

Comparison of liver biopsies before and after direct-acting antiviral therapy for hepatitis C and correlation with clinical outcome

Direct-acting antivirals (DAA) have replaced interferon (IFN)-based therapies for hepatitis C virus. In this retrospective clinical study, we examined differences in histopathologic features in paired liver biopsies collected from the same patient before and after DAA and correlated these findings with clinical outcome. Biopsies (n = 19) were evaluated by quantitative imaging analysis to measure steatosis and fibrosis. Most patients had decreased steatosis in their post-treatment, follow-up biopsies. However, one patient had a striking increase in steatosis (from 0.86 to 6.32%) and later developed decompensated cirrhosis and hepatocellular carcinoma (HCC). This patient had a marked increase in fibrosis between biopsies, with a CPA of 6.74 to 32.02. Another patient, who already had bridging fibrosis at the time of her pre-treatment biopsy, developed cholangiocarcinoma after DAA. Even though the overall inflammatory activity in the post-treatment biopsies significantly decreased after treatment, 60% of patients had persistent portal lymphocytic inflammation. In summary, DAAs decreased steatosis and hepatic inflammation in most patients, although some may have persistence of lymphocytic portal inflammation. Patients known to have advanced fibrosis at treatment initiation and who have other risk factors for ongoing liver injury, such as steatosis, should be followed closely for the development of adverse outcomes, such as portal hypertension and primary liver cancers.

Association Between Body Mass Index and Aggressive Features of Differentiated Thyroid Cancer

Background: Obesity is recognized as a risk factor for several types of cancers, including differentiated thyroid cancer (DTC). However, the association between obesity and aggressiveness of DTC is controversial. The aim of this study was to assess the relationship between body mass index (BMI), aggressive clinicopathological features of DTC and response to therapy in Saudi population. Methods: We evaluated 209 patients retrospectively who underwent total thyroidectomy at a referral center and diagnosed with DTC. Patients were stratified into 2 groups based on their BMI: non-obese (< 30 kg/m2), and obese (≥ 30 kg/m2). Pathological aggressiveness of DTC as well as clinical outcome were evaluated according to the 2015 American Thyroid Association (ATA) guideline. Data were described as mean ± SD and the categorical data as frequency percent. Mann Whitney test measured the difference in medians of all the metric variables and Chi-square test was applied for the categorical data to measure the intergroup difference between obese and non-obese binary dependent variable. All the inferences were carried out at 95% confidence interval in SPSS 25.0 software. Results: One-hundred twenty (57.4%) of our cohort were obese. Obesity was significantly more common in females (61.7%) than males (29.6%); (p=0.002). There were no differences in histopathological features between the non-obese and obese patients, including tumor size (2.3 ± 1.7 cm vs. 2.5 ± 2.1 cm, respectively, P-value = 0.812), extrathyroidal extension (16.9 % vs. 22.4 %, respectively, P-value=0.336), vascular invasions (25 % vs 18.4 %, respectively, P-value= 0.263) and lymph nodes metastasis (N1a 19.3 % vs 11.6 %, N1b 12.0 % vs. 10.7 % respectively, with P-value = 0.289), were shown between the two groups. In addition, no differences were evident in the ATA risk of recurrence (P-value = 0.843), TNM stage (P-value= 0.797), response to therapy (P-value= 0.252) and survival (P-value= 0.389) across the two groups. Conclusion: No association between BMI and DTC aggressiveness were found in our study population of Saudi patients. In addition, no association were demonstrated between BMI and response to therapy in DTC. These findings suggest that BMI may not be an independent risk factor for aggressiveness in DTC and that other traditional clinicopathological factors should be applied for risk assessment.

Effects of concomitant obesity and diabetes on the aggressiveness and outcomes of differentiated thyroid cancer patients.

Obesity and diabetes are the risk factors for cancer development including differentiated thyroid cancer (DTC). Contradictory accumulated data indicates the possible negative effects of obesity and hyperglyceamia as a factor for aggressiveness of DTC. The aim of the present study is to investigate the association of high body mass index (BMI) and presence of type 2 diabetes mellitus (T2DM) on the histological aggressiveness and clinical outcomes in DTC patients followed for over 4 years in a single center. Consequative 526 DTC patients who had undergone total thyroidectomy and/or radioactive iodine (RAI) ablation were reviewed retrospectively. Patients were divided into groups based on their BMI: normal weight, overweight, obese and also were evalauted in 3 groups presence of diabetes, prediabetes and nomoglyceamia. Histological aggressiveness of DTC at the time of diagnosis and clinical response at the time of last clinical visit were reassessed according to the criteria suggested by ATA 2015 guideline. No differences in histopathologic features, risk of recurrence, cumulative dose of RAI ablation and prevalence of 131I avid metastatic disease were demonstrated among the groups both classified according to BMI and hyperglycemia. Mean of 3.4 year follow-up also showed no differences in the clinial repsonse to therapy and percentage of nonthyroid primary cancer in DTC patients. In this retrospective study we demonstrated that obesity and T2DM have no additive effect on DTC aggressiveness and response to therapy. DTC patients with obesity and diabetes can be treated according to present guidelines without requirement for spesific attention.

Strain differences in histopathological features of lymphoid tissues of SD and F344 rats in a T cell-dependent antibody response assay of cyclophosphamide.

When conducting histopathological evaluation of lymphoid tissues, it is necessary to know the variability and strain differences in histological features of different sites of lymphoid tissues. To investigate in detail the variability of lymphoid tissues and strain differences of control rats as well as those of immune reactivity and sensitivity to immunosuppression, we performed a histopathological analysis of various lymphoid tissues in conjunction with the evaluation of immune function in a T cell-dependent antibody response (TDAR) assay with cyclophosphamide (CP) in Sprague Dawley (SD) and F344 rats. Six-week-old male SD and F344 rats were orally treated with CP at 0 (control) or 4 mg/kg/day for 28 days; keyhole limpet hemocyanin (KLH) was introduced intravenously on Days 14 and 23, and the serum concentrations of anti-KLH antibodies were measured. HE staining and immunohistochemistry for T-cell (CD3) and B-cell (CD45RA) markers were performed using tissues from the spleen, thymus, and various lymph nodes. In CP-treated rats of both strains, decreased concentrations of anti-KLH antibodies were observed. Histopathological analysis revealed decreased lymphocytes mainly in the B-cell area, and these changes induced by CP treatment were more prominent in the F344 rats than in the SD rats. The present study also demonstrated that some of the lymphoid tissues of the control F344 rats were less developed than those of the control SD rats, suggesting that F344 rats might be easily affected by CP-induced immunosuppression. This information concerning rat strain differences in lymphoid tissues will be useful in histopathological evaluation for drug-induced immunotoxicity.

Association of Clinicopathologic and Molecular Markers on Stage-specific Survival of Right Versus Left Colon Cancer

BackgroundPrevious studies have shown that variability in molecular markers correlates with poorer survival outcomes in patients with right-sided colon cancer (RCC) compared with left-sided colon cancer (LCC). However, several studies have shown conflicting results when examined stage for stage. We examined RCC and LCC to assess for differences in histopathologic features and overall survival (OS). Materials and MethodsThe National Cancer Database was used to identify patients with RCC and LCC from 2004 to 2013. A propensity-adjusted analysis evaluating the association between the primary site and OS was performed. ResultsOf the 422,443 patients identified, 54.7% had RCC and 45.3% had LCC. For all stages, the patients with RCC were older, had more poorly differentiated tumors, and had a greater degree of microsatellite instability compared with those with LCC. Patients with RCC also had more KRAS mutations than did those with LCC. RCC patients had poorer 3- and 5-year OS at all stages, especially stage 3 (62% vs. 73% and 50% vs. 62%, respectively; P < .001). The median OS was 77.5 months for LCC and 62.3 months for RCC (P < .001). ConclusionThe present study is one of the largest studies demonstrating that RCC and LCC are different biologic entities. Patients with RCC had significantly greater rates of microsatellite instability for all stages, which has been previously shown to be prognostically advantageous. However, the results of the present study showed poorer OS at every disease stage for RCC compared with LCC. These factors have important implications for the further use of targeted therapies in the treatment of advanced colon cancer.

Preeclampsia with and without intrauterine growth restriction–Two pathogenetically different entities?

ABSTRACTObjective: The objective of this study is to determine the differences in histopathological features of basal decidua and placenta in cases of preeclampsia with or without fetal intrauterine growth restriction (IUGR). Methods: A prospective case–control study included a study group consisting of 30 pregnant women with preeclampsia completed by cesarean section (CS), in 19 of whom preeclampsia was associated with IUGR, and in 11 it was not. The control group consisted of 20 healthy pregnant women delivered by elective CS. Placentas and samples of placental bed obtained during CS were histopathologically (HP) analyzed after hematoxylin–eosin staining and immunohistochemical labeling of Cytokeratin 7 (CK7) trophoblastic cells in decidua. Results: Regarding the HP changes in the spiral arteries in preeclampsia, the most frequent features were inadequate transformation of spiral arteries with poor trophoblastic invasion (70.0%) and fibrinoid necrosis of the media (66.7%), and rarely acute atherosis (33.3%) and thrombosis (30.0%). Villous hypermaturity was more frequently found in placentas of patients with preeclampsia with IUGR (p < 0.05), while there were no differences between subgroups of preeclampsia with and without IUGR regarding some of HP alterations of placental bed. Conclusion: Alterations of the placental bed in terms of decidual vasculopathy are more the characteristics of the preeclampsia itself than IUGR, while changes in placental villi primarily follow the presence of IUGR, which could indicate that preeclampsia with and without IUGR are two pathogenetically different entities.

Biochemical Profile of Nonalcoholic Fatty Liver Disease Patients in Eastern India with Histopathological Correlation.

Aminotransferase assay is often used as a screening test as well as an endpoint for resolution of disease in nonalcoholic fatty liver disease (NAFLD). Aim of the study was to evaluate the relationship of transaminase level with metabolic variables and histology in NAFLD. Single center observational study was conducted in a gastroenterology clinic at Cuttack in coastal Odisha. Subjects were consecutive patients presenting with functional bowel disease and undergoing abdominal sonography. All participants were evaluated for the presence of metabolic syndrome (MS), insulin resistance, liver function test and lipid profile. Various parameters were compared between NAFLD subjects and controls. 53.5% of NAFLD had normal serum transaminases, whereas 20.8% of healthy controls had transaminitis. NAFLD patients had significantly higher BMI, fasting plasma glucose, serum transaminases, serum triglycerides, serum insulin and homeostatic model assessment (HOMA) IR than controls. NAFLD patients who had transaminitis had significantly higher incidence of MS and higher mean HOMA IR than those without. There was no significant difference in histopathological features between NAFLD with and without transaminitis. To conclude, over half of NAFLD subjects do not have transaminitis while transaminitis is present in a fifth of healthy people without fatty liver. Hence serum transaminase should not be used as screening test for NAFLD. NAFLD patients with transaminitis had a higher incidence of MS and insulin resistance than those without. However, there was no significant difference in histopathological features between these two groups.

Correlation of tumour response with starting tumour size and dose of tamoxifen in an N-methyl-N-nitrosourea (NMU)-induced rat mammary cancer model.

The aim of this preliminary study was to address variations of responses observed with different starting tumor sizes of 10 and 15 mm, and the effects of different doses of tamoxifen (TAM) on experimental rat mammary tumors. Thirty-five inbred female Sprague Dawley rats aged 43 days were administered with three weekly doses of N-methyl-N-nitrosourea (NMU) intraperitoneally (ip) at 50 mg/kg body weight. Animals were randomized (beginning from 10 mm tumor size) into four TAM-treated (50, 100, 200 and 500 μg/day) groups of six animals each, and another group (n=6) treated with TAM 100 μg/day at starting tumour size of 15 mm. The animals were treated by oral gavage daily for 8 weeks before sacrifice. Serum urea and creatinine, and overall physical tumor burden were significantly modulated in animals treated with variable doses of TAM compared to the untreated controls (n=5). Final body weight and tumor number were significantly different in the 10 mm-treated animals compared to those treated at 15 mm. There were no significant differences in histopathological features among all the groups. Our findings suggest the importance of standardizing tumour size and drug doses before initiation of treatment, particularly in the direct comparison of basic end-tumour physical parameters.

P-0221 - Differences in Histo-Pathological Features of Colo-Rectal Carcinoma Between Diabetics and Non-Diabetics

P-0221 - Differences in Histo-Pathological Features of Colo-Rectal Carcinoma Between Diabetics and Non-Diabetics

Natural enamel caries in polarized light microscopy: differences in histopathological features derived from a qualitative versus a quantitative approach to interpret enamel birefringence

Lesion area measurement of enamel caries using polarized light microscopy (PLM) is currently performed in a large number of studies, but measurements are based mainly on a mislead qualitative interpretation of enamel birefringence in a single immersion medium. Here, five natural enamel caries lesions are analysed by microradiography and in PLM, and the differences in their histopathological features derived from a qualitative versus a quantitative interpretation of enamel birefringence are described. Enamel birefringence in different immersion media (air, water and quinoline) is interpreted by both qualitative and quantitative approaches, the former leading to an underestimation of the depth of enamel caries mainly when the criterion of validating sound enamel as a negatively birefringent area in immersion in water is used (a current common practice in dental research). Procedures to avoid the shortcomings of a qualitative interpretation of enamel birefringence are presented and discussed.

Gastric hyperplastic polyps in post transplant patients: a clinicopathologic study

Gastric hyperplastic polyps in organ transplant recipients have been recently described; however, the clinical significance of hyperplastic polyps in this setting remains unclear. The aim of this study is to further characterize the clinical presentation and histopathology of gastric hyperplastic polyps in organ transplant recipients as compared to hyperplastic polyps in non-transplant individuals. All gastric hyperplastic polyps diagnosed in our institute from 1999 to 2005 were retrieved. Clinical data including endoscopic findings were reviewed. Twenty cases without history of transplantation were randomly selected for a control population. Hematoxylin and eosin and Genta stains were reviewed. 104 cases of gastric hyperplastic polyps were identified. Sixteen (15%) had a history of solid organ (one liver/kidney, four livers, one lung, one kidney, one kidney/pancreas, three hearts) or bone marrow transplantation (five). The average time after transplantation was 28 months. Signs/symptoms leading to endoscopy were more frequently nausea/vomiting in transplant patients as compared to bleeding/hematemesis/anemia in non-transplant patients. The transplant patients tended to be younger with a reversed M:F ratio, but age was the only demographic factor that was statistically significant. There was no difference in polyp size, location and number. Histologically, no difference was observed in the frequency of active inflammation, Helicobacter pylori infection or intestinal metaplasia. Dysplasia was not present in any of the cases. None of the patients had a history of polyposis syndrome. In conclusion, a significant percentage of gastric hyperplastic polyps (15%) were from organ transplant patients, further suggesting a strong association of gastric hyperplastic polyps with transplantation. The younger age in the transplant group may be explained by the nature of the cohort qualified for transplantation. While no statistically significant differences in histopathologic features were found between transplant and non-transplant groups, analysis was limited by small case numbers. Overall, gastric hyperplastic polyps in the post transplant setting is a common, but under-recognized entity and merits further clinicopathologic analysis.

Inflammatory myofibroblastic tumor of the ulnar nerve

Inflammatory myofibroblastic tumors with involvement of cranial and peripheral nerves are exceedingly rare. The authors present the case of a 67-year-old man with an inflammatory myofibroblastic tumor of the left ulnar nerve, which was identified intraoperatively and mimicked a malignant neoplastic lesion. Histopathological examination revealed loosely structured fibrous tissue and collagen deposits intermingled with patchy infiltrates of lymphocytes, plasma cells, and histiocytes penetrating the endo- and epineurium of the affected nerve fascicles. There was strong expression of vimentin and actin in spindle cells throughout the lesion. The histiocytes were CD68- and major histocompatibility complex class II-positive, but lacked CD1a expression. A review of the literature revealed nine histopathologically confirmed cases of inflammatory myofibroblastic tumors involving peripheral or cranial nerves in which slight differences in histopathological features and surgical management were found, which are discussed here.

Histopathological Features of the Resected Left Atrial Appendage as Predictors of Recurrence After Surgery for Atrial Fibrillation in Valvular Heart Disease

A histopathological assessment of left atrial appendages (LAA) resected during surgical treatment for atrial fibrillation (AF) was made, with the aim of improving the prediction of postoperative AF recurrence. This clinicopathological study involved 57 surgical cases of valvular AF and 34 age- and sex-matched control autopsy cases with a history of sinus rhythm. LAA from the cases with valvular AF showed greater hypertrophy of cardiomyocytes (p<0.0001), greater nuclear enlargement (p<0.0001), more bizarre nuclei (BN; p<0.0001), and more intercellular fibrosis (ICF; p<0.001). Partial disarray of cardiomyocytes and fatty infiltration were recognized in both the AF and control groups. Thirty-seven cases had maintained sinus rhythm after surgery from 7 months to 10 years. AF recurred within a month of surgery in 17 and after a month in 3; there was no significant difference in histopathological features between them. These 20 cases had more cellular hypertrophy (p<0.025), nuclear enlargement (p<0.025), BN (p<0.01), and ICF (p<0.025) than those who maintained sinus rhythm after surgery. The histopathological findings for LAA reflected the underlying valvular diseases; however, the most reliable predictors of postoperative AF recurrence were hypertrophy of cardiomyocytes, bizarre shaped nuclei, and extensive ICF.

Glomerular expression of C-C chemokines in different types of human crescentic glomerulonephritis.

Crescentic glomerulonephritis (CGN) presents a rapidly progressive glomerulonephritis clinically, in which macrophages play a crucial role in the pathogenesis. However, the precise molecular mechanism of macrophage recruitment and activation has not been fully elucidated. C-C chemokines, monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1alpha and beta (MIP-1alpha and MIP-1beta), are major chemoattractants for macrophages. We attempted to study the expression of C-C chemokines and their correlation with CD68-positive macrophages in crescentic glomeruli to investigate further their possible roles in crescent formation and progression to fibrosis in different types of human CGN. The expression of MCP-1, MIP-1alpha, MIP-1beta and CD68 was detected in glomeruli with different forms of crescents (cellular, fibrocellular and fibrous crescents) by immunohistochemistry in serial sections of renal biopsies taken from 32 patients with biopsy-proven CGN including eight patients with anti-glomerular basement membrane (GBM) disease (type I CGN), 12 patients with immune complex-mediated CGN (type II CGN) and another 12 patients with pauci-immune CGN (type III CGN) enrolled in this study. Eight normal human kidneys were obtained from cadaveric renal transplant donors whose kidneys were technically unsuitable for transplantation, serving as controls. MCP-1, MIP-1alpha, MIP-1beta and CD68 were undetectable in glomeruli of normal kidney. In crescentic biopsies, MCP-1, MIP-1alpha, MIP-1beta and CD68 were detected in fibrocellular crescents and were even more prominent in cellular crescents, but were undetectable in fibrous crescents. Using consecutive sections for staining, it was demonstrated that a high proportion of infiltrating CD68-positive macrophages, mainly localized to the area of the expression of chemokines, were MCP-1, MIP-1alpha and MIP-1beta positive in crescents. Chemokines were expressed mainly by CD68-positive macrophages and parietal epithelial cells in crescents. The number of MCP-1- and MIP-1alpha-positive cells in glomeruli with cellular crescents was positively correlated with the number of CD68-positive cells (r = 0.568 and 0.749, respectively, both P < 0.01). The number of MCP-1- and MIP-1alpha-positive cells and the incidence of Bowman's capsule rupture in glomeruli of patients with type I CGN were higher than those of type II and type III CGN. These observations suggest that the expressed C-C chemokines, MCP-1, MIP-1alpha and MIP-1beta, may mediate the inflammatory process of crescent formation and progression to fibrosis. The strong correlation of MCP-1 and MIP-1alpha with infiltrating macrophages within glomeruli with cellular crescents suggested that these chemokines might be of particular importance for macrophage recruitment to this site. MCP-1 and MIP-1alpha were correlated to type I CGN with its more severe inflammatory course and worse prognosis. The variance of glomerular expression of C-C chemokines may contribute to the difference in histopathological features and prognosis in these three types of CGN.

Neutrophils Mediate Parenchymal Tissue Necrosis and Accelerate the Rejection of Complete Major Histocompatibility Complex-Disparate Cardiac Allografts in the Absence of Interferon-γ

A major feature of acute rejection of cardiac allografts is an intense mononuclear cell infiltration accompanied by interferon (IFN)-gamma production. In the current study we tested the role of IFN-gamma in acute rejection of allografts by comparing the histopathology of rejection in wild-type versus IFN-gamma-/- recipients of major histocompatibility complex-mismatched cardiac grafts. Wild-type recipients rejected the allografts at days 8 to 9 after transplant but rejection was accelerated 2 to 3 days in IFN-gamma-deficient recipients. During rejection in wild-type recipients, the allografts were heavily infiltrated with CD8+ T cells and other mononuclear cells. In contrast, allografts in IFN-gamma-deficient recipients had few T cells but an intense neutrophil infiltration accompanied by extensive graft parenchymal necrosis. No difference in expression levels of neutrophil chemoattractants including Groalpha/KC, MIP-2, GCP-2, and MIP-1alpha, was observed in allografts retrieved from wild-type and IFN-gamma-/- recipients. Depletion of neutrophils from IFN-gamma-deficient recipients delayed rejection until days 8 to 10 after transplant and restored the histopathology of acute allograft rejection to that observed in allografts rejected by wild-type recipients. These results indicate the potent regulatory properties of IFN-gamma during acute rejection directed at neutrophil infiltration into allografts and mediating graft tissue necrosis.