Peripheral T-cell lymphoma mimicking granulomatosis with polyangiitis.

Upper respiratory tract involvement is common in patients with granulomatosis with polyangiitis (GPA), but malignancies should be kept in mind in the differential diagnosis. A 68-year-old man was referred to rheumatology to investigate for GPA after nasal excisional biopsy. After careful radiologic and pathologic assessment, he was diagnosed with peripheral T­cell lymphoma, nasal type. This is a rare case of T­cell lymphoma in a patient who was referred as GPA.

Computed tomography characteristics of multiple myeloma and other osteolytic metastatic bone lesions.

BACKGROUND: Differentiation of multiple myeloma (MM) from osteolytic metastatic (OM) bone lesions may be critical in patients with lytic bone lesions but can be challenging for radiologists. PURPOSE: To determine whether computed tomography (CT) can be used to distinguish between MM and other OM bone lesions. MATERIAL AND METHODS: In this retrospective study, 320 lesions of 207 patients diagnosed with MM or OM, based on biopsy or clinical examination, were evaluated. Eight qualitative features were evaluated by two radiologists blinded to the diagnoses. The chi-square and Fisher exact tests, and logistic regression analysis, were used to evaluate the relationships between the CT findings and diagnoses. RESULTS: High-density areas were more common in OM than MM lesions (85.2% and 19%, P < 0.001), as were perilesional sclerosis (38.9% vs. 13.2%, P < 0.001), heterogeneity (on non-contrast CT images, 60% vs. 19.1%, P < 0.001; on contrast enhanced CT images, 80.6% vs. 28.2%, P < 0.001), and ill-defined margins (34.6% vs. 9.1%, P < 0.001). Similarly, OM lesions showed high-density areas more than MM in evaluation of skeletal system subgroups (vertebrae, 93.8% vs. 29.8%, P < 0.0001; thoracic cage bones, 69.6% vs. 19.2%, P < 0.001; pelvic bones and sacrum, 84.8% vs. 7.7%, P < 0.001; peripheral skeletal bones, 81.5% vs. 8.3%, P < 0.001). Logistic regression analysis revealed that the presence of a high-density area in the lesion increased the probability of a metastasis 25.88-fold (R2 = 0.516, P < 0.001). CONCLUSION: MM and OM lesions can be differentiated by CT; OM lesions exhibit high- density areas.

Penile lesion with inguinal adenopathy after intravesical Bacillus Calmette-Guerin instillation therapy.

Intravesical Bacillus Calmette-Guérin (BCG) is widely used as an adjuvant therapy in the treatment of non-muscle-invasive bladder cancer. BCG is generally well tolerated, though localized and systemic infectious complications may occur. Infection of the glans and inguinal adenopathy are rare local complications of intravesical BCG therapy. Traumatic urethral catheterization is one of the main causes. We report the case of a 75-year-old male who developed granulomatous balanitis and enlarged inguinal lymph nodes after five cycles of intravesical BCG treatment for transitional cell carcinoma of the bladder. Histology revealed giant cell granuloma. Oral antituberculous treatment was initiated with subsequent full recovery of penile lesions and adenopathy. Physicians who administer BCG must be familiar with the possible complications and their adequate management and should inform patients about the side-effects accordingly.

HHV-8 and EBV Positive Lymphoproliferative Disease: A Challenging Case.

Human herpes virus-8 (HHV-8) is linked to four lymphoproliferative diseases: primary effusion lymphoma, HHV-8 positive multicentric Castleman disease (MCD), HHV-8 positive diffuse large B cell lymphoma and HHV-8 positive germinotropic lymphoproliferative disorder (GLPD). The diagnosis of HHV-8 associated lymphoproliferative diseases is quite challenging because each entity is rare and has a wide morphological spectrum. Our aim is to emphasize the overlapping histopathological features of MCD and GLPD as well as to underline the importance of clinicopathological correlation in case these two entities cannot be distinguished by pathological examination. We present here a case of an 82-year-old male patient who was examined for weight loss and multiple lymphadenopathy. Histopathological examination of the axillary lymph node revealed lymphoid follicle structures of varying shapes and sizes, including some atrophic germinal centers. Plasmablast-like cells were notable in some of these areas. HHV-8 and Epstein Barr Virus (EBV) positivity were noted in some of these cells and in a small number of cells in the mantle zone. Based on these findings; a diagnosis of "HHV-8 and EBV positive lymphoproliferative disease" was established. Since HHV-8 positive MCD and GLPD have similar histopathological features, it may not be possible to distinguish these two entities by histopathological examination only. At this point, the importance of clinicopathological correlation becomes more evident, especially in the determination of the treatment protocol to be applied to the patient.

Effect of Local Tranexamic Acid on the Quality of Bone Healing in a Rat Spinal Fusion Model.

Introduction: The use of the antifibrinolytic agent tranexamic acid has positive effects on bleeding control, but our knowledge is still limited regarding how fibrinolysis suppression changes the process of bone formation and the quality of bone. Because of the several side effects of systemic tranexamic acid, topical usage has been established in several procedures. This study aimed to investigate the effect of local tranexamic acid on vertebral fusion by using macroscopic, radiologic, and microscopic techniques. We also attempted to determine the safe dose range in case some doses had negative effects on fusion. Methods: Twenty-eight Wistar albino rats underwent intertransverse fusion. All rats were randomized into four groups: groups treated with local tranexamic acid doses of 1 mg/kg (D1), 10 mg/kg (D10), and 100 mg/kg (D100) and the control group with no drug (D0). At the end of the eighth week, all rats were sacrificed for evaluation in terms of palpation, mammography, and histopathologic analysis. Results: The manual palpation results presented with lower fusion rates in D10 and D100 groups than in the control group. Radiological examination results were significantly higher in the control group. The histopathologic examination revealed no significant differences between groups in the percent of new bone formation. Conclusions: Our results showed that local administration of tranexamic acid reduced the quality and stability of fusion without a delay in bone formation. However, doses of 1 mg/kg did not reduce the stability in the palpation test. Our findings suggest that 1 mg/kg dose is a critical threshold above which tranexamic acid reduced the bone healing process of fusion and that surgeons should consider the doses of local tranexamic acid during surgery.

Assessment of Bone Marrow Biopsy and Cytogenetic Findings in Patients with Multiple Myeloma

Objective: Multiple myeloma (MM) is a malignant condition characterized by the accumulation of malignant plasma cells. Although MM remains incurable, the survival of MM patients has improved considerably due to the application of autologous stem cell transplantation, novel agents, and advanced treatment strategies. This study aimed to determine the cytogenetic characterization and bone marrow (BM) features of Turkish patients with MM. Materials and Methods: Eighty-five MM patients were admitted to Dokuz Eylül University Hospital in Turkey. BM samples of these MM patients were subjected to cytogenetic analyses at diagnosis and during therapy as a part of therapeutical and clinical evaluation. A complete cytogenetic study was performed using the G-banding technique. Fluorescence in situ hybridization (FISH) analysis was performed using cytoplasmic immunoglobulin. The degree of BM fibrosis was determined using reticulin histochemical staining. We determined the percentage of BM plasma cells based on the extent of CD38 staining. Results: Eighty-five MM patients were retrospectively identified between 2015 and 2021. The median age was 63 (38-90) years. Of the 85 patients, 60 (70.6%) were male and 25 (29.4%) were female. Seventy-two (84.7%) cases had BM fibrosis at the time of diagnosis. The most common was grade 2 fibrosis, recorded in 35 cases (41.2%). About 72.9% of the patients showed more than 50% plasma cells. FISH analysis indicated the presence of abnormal chromosomes in 37% (32/85) of the patients. The most frequent abnormality was Immunoglobulin heavy-chain (IGH) translocation (21.3%). Conclusion: Subgroup analysis of IGH mutations is crucial in the identification of high-risk MM patients. We believe that our study will contribute to the determination of BM biopsy and cytogenetic features of MM patients in our country.

Plasma Concentrations and Cancer-Associated Mutations in Cell-Free Circulating DNA of Treatment-Naive Follicular Lymphoma for Improved Non-Invasive Diagnosis and Prognosis.

Follicular lymphoma (FL) is the second most frequent non-Hodgkin lymphoma accounting for 10-20% of all lymphomas in western countries. As a clinically heterogeneous cancer, FL occasionally undergoes histological transformation to more aggressive B cell lymphoma types that are associated with poor prognosis. Here we evaluated the potential of circulating cell-free DNA (cfDNA) to improve the diagnosis and prognosis of follicular lymphoma patients. Twenty well-characterized FL cases (13 symptomatic and 7 asymptomatic) were prospectively included in this study. Plasma cfDNA, formalin-fixed paraffin-embedded (FFPE) tumor tissue DNA, and patient-matched granulocyte genomic DNA samples were obtained from 20 treatment-naive FL cases. Ultra-deep targeted next-generation sequencing was performed with these DNA samples by using a custom-designed platform including exons and exon-intron boundaries of 110 FL related genes. Using a strict computational bioinformatics pipeline, we identified 91 somatic variants in 31 genes in treatment-naive FL cases. Selected variants were cross-validated by using PCR-Sanger sequencing. We observed higher concentrations of cfDNA and a higher overlap of somatic variants present both in cfDNA and tumor tissue DNA in symptomatic FL cases compared to asymptomatic ones. Variants known to be associated with FL pathogenesis such as STAT6 p.D419 or EZH2 p.Y646 were observed in patient-matched cfDNA and tumor tissue samples. Consistent with previous observations, high Ki-67 staining, elevated LDH levels, FDG PET/CT positivity were associated with poor survival. High plasma cfDNA concentrations or the presence of BCL2 mutations in cfDNA showed significant association with poor survival in treatment-naive patients. BCL2 mutation evaluations in cfDNA improved the prognostic utility of previously established variables. In addition, we observed that a FL patient who had progressive disease contained histological transformation-associated gene (i.e. B2M and BTG1) mutations only in cfDNA. Pre-treatment concentrations and genotype of plasma cfDNA may be used as a liquid biopsy to improve diagnosis, risk stratification, and prediction of histological transformation. Targeted therapies related to oncogenic mutations may be applied based on cfDNA genotyping results. However, the results of this study need to be validated in a larger cohort of FL patients as the analyses conducted in this study have an exploratory nature.

Whole Transcriptome Sequencing Reveals Cancer-Related, Prognostically Significant Transcripts and Tumor-Infiltrating Immunocytes in Mantle Cell Lymphoma.

Mantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin lymphoma (NHL) subtype characterized by overexpression of CCND1 and SOX11 genes. It is generally associated with clinically poor outcomes despite recent improvements in therapeutic approaches. The genes associated with the development and prognosis of MCL are still largely unknown. Through whole transcriptome sequencing (WTS), we identified mRNAs, lncRNAs, and alternative transcripts differentially expressed in MCL cases compared with reactive tonsil B-cell subsets. CCND1, VCAM1, and VWF mRNAs, as well as MIR100HG and ROR1-AS1 lncRNAs, were among the top 10 most significantly overexpressed, oncogenesis-related transcripts. Survival analyses with each of the top upregulated transcripts showed that MCL cases with high expression of VWF mRNA and low expression of FTX lncRNA were associated with poor overall survival. Similarly, high expression of MSTRG.153013.3, an overexpressed alternative transcript, was associated with shortened MCL survival. Known tumor suppressor candidates (e.g., PI3KIP1, UBXN) were significantly downregulated in MCL cases. Top differentially expressed protein-coding genes were enriched in signaling pathways related to invasion and metastasis. Survival analyses based on the abundance of tumor-infiltrating immunocytes estimated with CIBERSORTx showed that high ratios of CD8+ T-cells or resting NK cells and low ratios of eosinophils are associated with poor overall survival in diagnostic MCL cases. Integrative analysis of tumor-infiltrating CD8+ T-cell abundance and overexpressed oncogene candidates showed that MCL cases with high ratio CD8+ T-cells and low expression of FTX or PCA3 can potentially predict high-risk MCL patients. WTS results were cross-validated with qRT-PCR of selected transcripts as well as linear correlation analyses. In conclusion, expression levels of oncogenesis-associated transcripts and/or the ratios of microenvironmental immunocytes in MCL tumors may be used to improve prognostication, thereby leading to better patient management and outcomes.

Challenges in the Diagnosis of Intraocular Lymphoma

Intraocular lymphomas are among the rare malignancies that present with a wide variety of clinical manifestations. Differential diagnosis can be very troublesome due to its mimicking nature, insidious disease onset, and partial treatment response to steroids. The most important step in diagnosis is a high index of suspicion. Signs of the disease are now easier to detect using multimodal imaging techniques. In this case series, we reviewed the clinical characteristics of two women aged 70 and 71 years and a 72-year-old man with intraocular lymphoma and described their multimodal imaging findings in detail. Bilateral eye involvement was present in all three cases at our first ophthalmological examination. While the disease first presented with ocular involvement in two of the three cases, ocular involvement was detected seven years after initial heart involvement in one patient. All three patients had diffuse large B-cell lymphomas (one diagnosed with retinal biopsy, one with conjunctival biopsy, and the remaining with stereotactic brain biopsy). Intraocular lymphoma should be diagnosed and treated using a multidisciplinary approach, and we share our experience in this case series.

Three cases of immunoglobulin G4-related respiratory disease with uncommon imaging findings.

BACKGROUND: Immunoglobulin G4-related disease (IgG4-RD) is a rare multisystemic idiopathic fibroinflammatory disorder. The rare form of IgG4-RD with isolated thorax involvement is called immunoglobulin G4-related respiratory disease (IgG4-RRD). IgG4-RRD, which is reported in a limited number of cases in the literature, can be categorized into four types on the prevalent chest computed tomography (CCT) findings: solid nodular, round-shaped ground-glass opacity, alveolar interstitial, and bronchovascular. Solid nodular form of IgG4-RRD with mass-like lesions is sporadic and described in the literature with a small number of case reports. OBJECTIVES/METHODS: We aim to present the radiologic, pathologic, and clinical findings of three cases of IgG4-RRD mimicking lung cancer. RESULTS: In all three patients, IgG4-RRD occurred with mass-like lesions in the thorax. In case-1 and 2, CCT showed multiple, nodular lesions and multiple mediastinal lymph nodes. On positron emission tomography with 2-deoxy-2-[fluorine-18] fluoro- D-glucose integrated with computed tomography (18F-FDG PET/CT), the masses showed increased 18F-FDG uptake in case-2 and 3. The gold standard histopathological verification for IgG4-RRD was provided for all cases. CONCLUSIONS: IgG4-RD is an immune-mediated condition comprised of a collection of disorders that share particular pathologic, radiologic, serologic, and clinical features. Isolated IgG4-RRD is rarely seen and is available in the literature as case reports. IgG4-RRD, which can make lung involvement in different patterns, rarely appears with mass-like lesions. Still, IgG4-RRD must be considered in the differential diagnosis of mass lesions detected in CCT. Laboratory, radiological, and histopathological findings of the disease should be evaluated together for an accurate diagnosis.

UNUSUAL PRESENTATIONS OF LMNA-ASSOCIATED LIPODYSTROPHY WITH COMPLEX PHENOTYPES AND GENERALIZED FAT LOSS: WHEN THE GENETIC DIAGNOSIS UNCOVERS NOVEL FEATURES.

OBJECTIVE: Lipodystrophy represents a group of rare diseases characterized by loss of body fat. While patients with generalized lipodystrophy exhibit near-total lack of fat, partial lipodystrophy is associated with selective fat loss affecting certain parts of the body. Although classical familial partial lipodystrophy (FPLD) is a well-described entity, recent reports indicate phenotypic heterogeneity among carriers of LMNA pathogenic variants. METHODS: We have encountered 2 unique cases with complex phenotypes, generalized fat loss, and very low leptin levels that made the distinction between generalized versus partial lipodystrophy quite challenging. RESULTS: We present a 61-year-old female with generalized fat loss, harboring the heterozygous pathogenic variant p.R541P (c.1622G>C) on the LMNA gene. The discovery of the pathogenic variant led to correct clinical diagnosis of her muscle disease, identification of significant heart disease, and a recommendation for the implantation of a defibrillator. She was able to start metreleptin based on her generalized fat loss pattern and demonstration of the genetic variant. Secondly, we report a 40-year-old Turkish female with generalized fat loss associated with a novel heterozygous LMNA pathogenic variant p.K486E (c.1456A>G), who developed systemic B cell follicular lymphoma. CONCLUSION: Clinicians need to recognize that the presence of an LMNA variant does not universally lead to FPLD type 2, but may lead to a phenotype that is more complex and may resemble more closely generalized lipo-dystrophy. Additionally, providers should recognize the multisystem features of laminopathies and should screen for these features in affected patients, especially if the variant is not at the known hotspot for FPLD type 2.

Prognostic Factors in Elderly Patients with Diffuse Large B-Cell Lymphoma and Their Treatment Results

Objective: Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma (NHL). The treatment of older NHL patients has always been a struggle; however, treatment statistics have begun showing favorable results similar to those of younger DLBCL patients thanks to newer treatment protocols. Here, we analyze the progress of our own elderly DLBCL patients who were followed between 2000 and 2016 in our center. Materials and Methods: Eighty-seven DLBCL patients, who were diagnosed and treated in the Dokuz Eylül University Department of Hematology between 2000 and 2016, were included in this study. Median age was 72 (65-89) years and 13 (14.9%) patients were older than 80 years. Results: Median follow-up time was 19 months and 45 patients (51.7%) died during the follow-up period. Median overall survival (OS) was 55 months and median progression-free survival was calculated as 27 months. Sixty-three patients (72.4%) received standard R-CHOP therapy. Complete response was seen in 46 (52.9%) patients. The median survival time for patients who had complete response was 136 months (p<0.001); however, OS was not statistically different between older (>80 years) and younger patients (p=0.236). Conclusion: According to our findings, we think that being able to complete standard R-CHOP therapy is vital for the survival rate of elderly DLBCL patients.

Fibrosis in Hodgkin and non-Hodgkin lymphomas.

There is little quantitative information about the amount of fibrosis in lymphomas. The aim of the present study was to investigate the amount of fibrosis in lymphomas and to highlight the relationship between fibrosis and mast cells, the key players of fibrosis. Tissue sections of 60 patients with diagnosis of lymphoma were reevaluated for classification. The mean fibrotic-stained area percentage (F-SAP) was determined in van Gieson-stained digital images using image analysis (Mediscope, Dokuz Eylul University, Clinical Engineering, Turkey). Mast cells were visualized using streptavidin peroxidase immunohistochemistry with anti-tryptase staining. Twenty-seven (44%) cases were Hodgkin's lymphoma (HL). F-SAP was 11.09+/-8.96 and 1.72+/-1.76 for HL and non-HL cases (Mann-Whitney U, p<0.000), and the mean mast cell count (MMCC) was 24.63+/-13.58 and 8.03+/-8.07, respectively (Mann-Whitney U test, p<0.000). There was a significant difference between F-SAP and MMCC concerning different types of lymphomas (Kruskal-Wallis test, p>0.000). F-SAP was highest in nodular sclerosis HL, and MMCC was highest in mixed cellular HL. There was a strong positive correlation between MMCC and F-SAP (Pearson Correlation test, p<0.000, r=0.51). These results suggest that the amount of fibrosis demonstrates differences in subtypes of lymphomas, and mast cells are increased in fibrosing lymphomas. However, it seems likely that more than one cell type is involved.

Renal failure in high altitude: renal functions, renal pathology and bone mineralization in rats with ablation nephropathy at 1200 m altitude.

The effect of altitude on renal failure and bone mineralization is not well known. This topic is studied in a 5/6 nephrectomy rat model. After hemoglobin, creatinine clearance and proteinuria were determined in 28 Wistar rats. Two 5/6 nephrectomy (Nx1-Nx2, n=7 each) and two sham (Sh1-Sh2, n=7 each) groups were formed. The Nx1-Sh1 and Nx2-Sh2 groups were kept at sea level and at 1200 m altitude, respectively. The same analyses were performed after 3 months just before sacrifices in order to harvest kidneys and femurs for histopathologic examination. Hemoglobin, creatinine clearance, and proteinuria were similar in all groups at the onset. Final hemoglobin was higher in Nx2-Sh2, but only Sh2 vs. Sh1 was significant (p=0.001). Creatinine clearance decreased (p=0.001 for Nx1) and proteinuria increased (p=0.002 for Nx1 and p=0.005 for Nx2) after 5/6 nephrectomy, but Nx1 vs. Nx2 was similar. Histopathological changes in the remnant kidneys were prominent, but Nx1 vs. Nx2 was not different. Although the relative osteoid volume increased in Nx groups, only Nx1 vs. Sh1 was different (p=0.006). In conclusion, exposure to 1200 m altitude, compared to the sea level, preserved the creatinine clearance better in 5/6 nephrectomized rats. No change was observed in proteinuria, renal histopathology, and bone mineralization.

[Quantification of papain-induced rat osteoarthritis in relation to time with the Mankin score]. / Siçanlarda papainle olusturulan osteoartritin Mankin skoru ile zamana bagli derecelendirilmesi.

OBJECTIVES: The aim of this study was to evaluate structural changes in relation to time with the use of the Mankin scoring system in papain-induced rat osteoarthritis. METHODS: Osteoarthritis was induced in 21 male Wistar rats by injecting an admixture of 4% papain (10 microl) and its activator 0.03 M cycteine (10 microl) into the right knee joints on the first, fourth, and seventh days. The same volume of sterile saline solution was injected into the left knees as controls. The rats were assigned to three groups equal in number and were sacrificed under high-dose ether anesthesia after one, two, and four weeks of the last papain injection, respectively. The study and control knee joints were removed and histologic changes in cartilage structure were assessed and quantified with the modified Mankin scoring system. RESULTS: Histologically, all papain injected knees exhibited irregularity and fibrillation in the superficial layer, decreased cell count and multilayering in transitional and radial zones, and no pannus formation. The modified Mankin scores were significantly higher compared to the control knees in all the groups (p<0.05), being 4.3+/-0.9, 6.9+/-1.3, and 10.4+/-1.9 in diseased knees, and 2.7+/-0.5, 4.0+/-0.8, and 4.4+/-1.0 in the control knees after one, two, and four weeks of the last papain injection, respectively. There was a significant difference between the Mankin scores of the rats sacrificed after one and four weeks of the last papain injection (p=0.0471). CONCLUSION: Findings observed after four weeks of papain injection seem to be consistent with early osteoarthritic changes. Our results may provide insight into therapeutic strategies for early osteoarthritis.

Indocyanine green angiographic features of systemic non-Hodgkin's lymphoma and bilateral choroidal involvement.

A 35-year-old man with systemic non-Hodgkin's lymphoma and bilateral choroidal involvement is described. Indocyanine green angiography depicts choroidal involvement much better than fluorescein angiography and seems to be superior in diagnosing and monitoring patients with systemic non-Hodgkin's lymphoma and choroidal involvement.

The Effect of Autologous Platelet Rich Plasma in the Treatment of Achilles Tendon Ruptures: An Experimental Study on Rabbits.

BACKGROUND: Achilles tendon ruptures are characterized by a long recovery period, high re-rupture rate and late return to work. To overcome these difficulties and augment tendon repair, many agents have been used. AIMS: To determine the effect of autologous platelet rich plasma (PRP) in the treatment of Achilles tendon ruptures in rabbits. STUDY DESIGN: Animal experimentation. METHODS: The study included 14 New Zealand albino rabbits that were divided randomly into 2 groups, A and B, each containing seven rabbits. On day zero, all 28 Achilles tendons were tenotomized and repaired. In group A, the tendons were injected with PRP post-surgery, whereas those in group B were left untreated. On day 28, the right tendons in both groups were examined histopathologically via both light and electron microscopy, and the left tendons were subjected to biomechanical testing. RESULTS: The histological and biomechanical findings in both light and electron microscopy in group A were better than those in group B, but the difference was not significant. According to Tang's scale, the mean value in Group A was 3.57, while it was 3.0 in Group B. The mean value of Group A for the length of collagen bands was 48.09 nm while the mean value of Group B was 46.58 nm (p=0.406). In biomechanical tests, although stiffness values were higher in group A, the difference between groups was not significant. In addition, maximum load values did not differ between groups A and B. CONCLUSION: PRP had no effect on the healing process 28 days post-Achilles tendon rupture.

Effect of retinoic acid on oxygen-induced lung injury in the newborn rat.

Oxygen-induced lung injury is believed to lead to the development of bronchopulmonary dysplasia (BPD). To determine whether retinoic acid (RA) treatment prevents the development of BPD by minimizing lung injury, we investigated the effect of RA on the histopathologic characteristics of oxygen-induced lung injury in a newborn rat model. Eighteen rat pups were divided into three groups: room air-exposed control group (n=5), oxygen-exposed placebo group (n=7), and RA-treated oxygen-exposed group (n=6). Measurement of alveolar area, quantitation of secondary crest formation, microvessel count, evaluation of alveolar septal fibrosis, and smooth muscle actin (SMA) immunostaining were performed to assess oxygen-induced changes in lung morphology. Treatment of oxygen-exposed animals with RA resulted in a significant increase in mean alveolar area; however, it had no effect on the number of secondary crests and microvessel count. The degree of fibrosis and SMA expression showed a significant decrease in RA-treated animals. We conclude that RA treatment improves alveolar structure and decreases fibrosis in the newborn rat with oxygen-induced lung injury. Extrapolating these findings to humans, we speculate that similar treatment with RA may reduce lung injury in preterm infants at risk for BPD.

The role of endothelin receptor antagonism in collar-induced intimal thickening and vascular reactivity changes in rabbits.

Intimal thickening, due to smooth muscle cell migration and proliferation, is considered to be one of the major components of vascular proliferative disorders such as atherosclerosis and restenosis. One experimental model, resulting in intimal thickening in the rabbit, involves placing a silicon collar around the carotid artery, and is used in this study. Endothelin is known to act as a strong mitogen and to stimulate smooth muscle cell proliferation and migration. We investigated the contribution of endothelin to the development of collar-induced intimal thickening and the effects of TAK-044, (5 mg kg(-1) daily, s.c.), a non-selective ET(A)/ET(B) receptor antagonist, on intimal thickening and vascular reactivity changes in the collared rabbit carotid artery. Endothelin levels and the intimal cross-sectional area, as well as the ratio of intimal area to media (index), increased significantly in collared arteries as compared with those in sham-operated arteries. TAK-044 significantly inhibited intimal thickening and also decreased the index without affecting increased endothelin levels in collared arteries. Vascular reactivity changes in response to collaring produced predictable effects, such as decreased contractile responses to vasoconstrictor agents and increased sensitivity to serotonin (5-hydroxytryptamine, 5-HT). In terms of contractile responses in this model, TAK-044, in particular, did not affect collar-induced vascular reactivity changes. These results suggest that endothelin may be involved in the pathogenesis of collar-induced intimal thickening. As an endothelin receptor antagonist, TAK-044 may potentially be beneficial in the treatment of atherosclerosis.

Association of macrophages, mast cells and eosinophil leukocytes with angiogenesis and tumor stage in non-small cell lung carcinomas (NSCLC).

The association between inflammatory cells, including tumor associated macrophage (TAM), mast cell (MC) and eosinophil leucocyte (EL) densities and angiogenesis, as well as the relation of TAM, MC and EL densities and angiogenesis to tumor stage were investigated in specimens of 63 non-small cell lung carcinoma (NSCLC). Fifteen cases were in stage I, 12 were in stage II, 33 were in stage III and 3 were in stage IV. ELs and MCs were identified by hematoxilen-eosin and toluidine-blue histochemical stains, respectively. TAMs were shown by immunohistochemistry for CD68. Microvessels demonstrated by immunohistochemistry for CD31 were quantified by a stereological method and vascular surface density (VSD) and microvessel number (NVES) were calculated. There was not any statistically significant correlation between tumor's stage and VSD, TAM and EL counts. MC count and NVES were found to be higher in early stages. VSD and NVES were not associated with EL, MC and TAM counts. The lack of consistent correlation of angiogenesis to the stage of disease in this study supports the view that tumor angiogenesis is not a significant prognostic factor in NSCLCs. The absence of correlation between MCs, ELs and TAM counts and angiogenesis and absence of any relation between ELs and TAMs and tumor stage are discordant with the results of some of the previous studies in NSCLCs and in other tumors. The differing results may be due to wide variations in methodologies which were used for demonstration of inflammatory cells and vessels and variations in the degree of activation and complexity of functions of these cells.