Reticular Fibrosis Research Articles

Relationship between reticular fibrosis with platelet surface markers (CD41A, CD42A, CD42B, CD61) and prognostic markers (WBC, PLT) in acute promyelocytic leukemia

Relationship between reticular fibrosis with platelet surface markers (CD41A, CD42A, CD42B, CD61) and prognostic markers (WBC, PLT) in acute promyelocytic leukemia

Peculiar hyper vascular manifestations in idiopathic multicentric castleman disease without tafro syndrome: a case report.

Castleman disease affects lymph nodes with abnormal cell growth. It has unicentric (single node) Castleman disease (UCD) and multicentric (multiple nodes) Castleman disease (MCD) forms. MCD is systemic, with diverse symptoms, necessitating systemic treatment. Idiopathic MCD (iMCD) clinical subtypes are divided into iMCD- not otherwise specified (NOS) and iMCD-TAFRO (thrombocytopenia, anasarca, fever, reticular fibrosis, organomegaly). UCD, iMCD-NOS, and iMCD-TAFRO mainly exhibit histopathology of hyaline vascular type, plasma cell type, and hyper vascular type, respectively. A 21-year-old female with no comorbidities presented to the outpatient department (OPD) with left inguinal swelling, gradually growing over four years, accompanied by fever and weight loss. Her past medical history included pulmonary TB 5 years prior and miscarriages. Vitals are within normal limits. Examination revealed a tender, nonreducible inguinal lump and a smaller neck swelling. Serological tests for infections were negative. Imaging revealed enlarged lymph nodes. Biopsy confirmed Castleman disease of the hyper vascular type. We performed surgical removal of the enlarged lymph nodes followed by close regular follow-up along with potential chemotherapy for relapse. Hyper vascular type of the lymph node histology in Idiopathic multicentric Castleman disease without TAFRO syndrome must be considered a differential diagnosis in lymphoproliferative disease.

Study on Damage of Myocardial Tissue Under Low-Dose Heart Irradiation in Rats

<h3>Purpose/Objective(s)</h3> Radiation induced heart damage (RIHD) is an important late toxicity of thoracic radiotherapy, which is closely relating with the fractional dose of radiotherapy. With the wide application of stereotactic body radiotherapy and hyperfractionated radiotherapy, the single dose and biological equivalent dose (BED) of the heart of exposure have increased when comparing with conventionally fractionated radiotherapy. However, the mean cardiac dose (MHD), which is frequently used clinically to ensure the control of cardiac damage, is continuously decreased to 26 Gy, 20 Gy, etc. There is still controversy about how much dose could control heart radiation damage better. In this study, 15 Gy/3f low-dose irradiation of the whole heart of rats, which BED is similar with 24 Gy/12f irradiation, is selected to explore the possibility and characteristics of RIHD occurrence, and explore the effect of combined recombinant human endostatin on myocardial damage. <h3>Materials/Methods</h3> 75 SD adult male rats were randomly divided into control (C group, E group, MHD₂₅ group) and experimental group (MHD₁₅ group, MHD_15+E group). The irradiation method was single dose 5 Gy/f, once per day, continuous irradiation 3d or 5d. After the irradiation, the E group and MHD_15+E group were given recombinant human endostatin 6mg/kg intraperitoneal injection, once per day, for 14 consecutive days. At 1, 3, and 6 months after intervention, 5 rats in each group were randomly selected for HE, Masson, and immunohistochemical CD34 microvessel staining, and Western Blot detected mitochondrial Complex II protein expression. Two-way ANOVA statistics. <h3>Results</h3> Compared with C group, edema and disorder of myocardial cells, infiltration of inflammatory cells and decrease of microvessel density was observed at 1 month after intervention in HE staining in MHD₁₅ and MHD_15+E group. The expression of complex II protein decreased at 6 months, and the degree of decrease was less than that in MHD₂₅ group (positive control group) (<i>P</i> < 0.05). The microvessel density was further decreased compared with 1 month. Myocardial fibrosis induced by 15 Gy/3f low-dose irradiation of SD rat heart mainly occurred at 6 months, which observed myocardial cord or reticular fibrosis and collagen deposition. Semi-quantitative analysis of myocardial collagen volume fraction CVF significantly increased (<i>P</i> < 0.001) in HE and Masson staining. Details is shown in the table below. Compared with C group, E group observed myocardial edema and decreased microvessel density. There was no significant difference between MHD₁₅ and MHD_15+E group. <h3>Conclusion</h3> Low dose irradiation of 15 Gy/3f (BED = 40 Gy) still cause myocardial fibrosis and damage of cardiac function in SD rats. RIHD were observed after 6 months, which was equal to about 1/5 of the rat's life span, and the time was delayed when compared with the time of RIHD caused by high dose irradiation. Cardiotoxicity was not increased significantly combining recombinant human endostatin on the basis of low-dose cardiac.

RECURRENT PNEUMOTHORACES AS A PRESENTING SYMPTOM OF NON-SPECIFIC INTERSTITIAL PNEUMONIA IN A YOUNG MALE PATIENT

SESSION TITLE: Fellows Diffuse Lung Disease Posters SESSION TYPE: Fellow Case Report Posters PRESENTED ON: October 18-21, 2020 INTRODUCTION: Nonspecific interstitial pneumonia (NSIP) is the second most common cause of the idiopathic interstitial pneumonias and is associated with various underlying conditions including connective tissue disorders, medications and infections1. We present an unusual case of biopsy-proven NSIP presenting as recurrent pneumothoraces in a young male. CASE PRESENTATION: We present a 17-year-old male with a history of gastroesophageal reflux and an adrenal neuroblastoma status post resection with subsequent extensive chemoradiation which was curative. Years later he experienced his first of 16 pneumothoraces, each treated with the placement of a chest tube leading to resolution without complication. He later developed worsening dyspnea on exertion that limited his daily activities triggering an outpatient evaluation in which a moderate restrictive pattern was noted on his pulmonary function tests (PFTs). He was subsequently referred to our interstitial lung disease clinic for further evaluation, where a CT chest revealed ground-glass opacities with minimal interstitial changes. His PFTs continue to decline as did his symptoms and following an extensive discussion and counseling on the risks, the patient opted to undergo a biopsy to obtain a definitive diagnosis. A bronchoscopy with cryobiopsies was performed and samples were taken of the right lung. Unfortunately, he experienced a complication in the form of a pneumothorax as a result of the procedure. A chest tube was immediately placed, and he was admitted for further medical management. Despite the placement of the chest tube, he had a persistent air leak and ultimately required a VATs with pleurodesis, which resulted in the resolution of the air leak. Surprisingly the histopathology of the samples obtained showed peribronchial lymphoid aggregates, reticular fibrosis, and non-specific interstitial pneumonia, with no evidence of significant honeycombing and was consistent with an overall diagnosis of NSIP. Following these findings, a serological workup was performed to evaluate for occult connective tissue disorders but was unremarkable. DISCUSSION: While some interstitial lung diseases have been associated with the development of a pneumothorax, it is an unusual prevailing symptom with an incidence rate of 7.9% noted in a recent study2. The pathogenesis of a secondary spontaneous pneumothorax (SSP) in these cases is unclear, but it is thought to be attributed to rupture of subpleural areas of honeycombing cysts2. CONCLUSIONS: We present an unusual case of a young male with biopsy-proven NSIP, who presented following multiple pneumothoraces and moderate restriction on PFTs. Given his continued decline he was started on steroids and immunosuppressive treatment but will likely require definitive therapy in the form of a lung transplant. Reference #1: Nayfeh AS, Moore DR. Nonspecific Interstitial Pneumonitis. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK518974. Reference #2: Porcel, J.M. (2018) Secondary spontaneous pneumothorax in idiopathic pulmonary fibrosis: Grim news. Respirology, 23: 448– 449. doi: 10.1111/resp.13253. DISCLOSURES: No relevant relationships by Sruti Brahmandam, source=Web Response No relevant relationships by Sravya Brahmandam, source=Web Response No relevant relationships by Sally Suliman, source=Web Response

PB2238 AGGRESSIVE SYSTEMIC MASTOCYTOSIS: A DIAGNOSTIC CHALLENGE IN A PATIENT WITH MYOTONIC DYSTROPHY TYPE 2

Background:Systemic mastocytosis (SM) is a clonal neoplastic disease of mast cells (MCs) with heterogeneous clinical presentations, different organ infiltration, and is often overlooked. The spectrum ranges from indolent to aggressive forms. SM could also be associated with myeloid and lymphoid hematologic diseases.Aims:We present a case where SM was misdiagnosed as a progression of myotonic dystrophy.Methods:A 55‐year‐old caucasian woman with known familial myotonic dystrophy type 2 (DM2) proven by CCTG‐repeat expansion in the ZNF9 gene was referred with a diagnosis of unclassified myeloproliferative neoplasm with 10% bone marrow (BM) blasts and mutations in KRAS, ASXL1 and RUNX1. In the last two months, she complained of weight loss, muscle weakness, and fever. Because of progressive dysphagia, enteral nutrition by percutaneous endoscopic gastrostomy tube (PEG) was initiated. Clinically, a body mass index (BMI) of 13.6 kg/m2, normal skin, and hepatosplenomegaly were seen. Hilar lymphadenopathy and pulmonary infiltrates were detected by CT‐scan. Laboratory analysis showed a WBC count of 39.80x109/L with left shift, Hb of 4.4 g/dl, platelets of 78x109/L, hypoalbuminemia, and an elevated lactate dehydrogenase. Rapid neurological deterioration is typical in myotonic dystrophy type 1, which is associated with a worse prognosis and is unusual for DM2 (Schoser B, Timchenko L.; Current Genomics; 2010). Curiously, DM2 was genetically proven.Results:Assessment of serum tryptase is part of our routine diagnostic work‐up for hematologic diseases and was 46.9 μg/L (reference range &lt;11 μg/l) in the patient. A repeat BM biopsy revealed a hypercellular marrow with delayed myelopoietic maturation and a normal blast count. There were peritrabecular conspicuous nodular areas with minimal reticular fibrosis. Therein, multifocal clustering of MCs (at least 15/cluster) co‐expressing CD2, CD25, CD117, and mast cell tryptase were detected. Cytogenetics were normal but the activating mutation KITD816 V was present.Thus, a diagnosis of SM could be made based on the major criterion (≥ 15 MC in clusters) and three minor criteria (the KIT mutation, CD25/CD2 co‐expression, serum tryptase &gt; 20 μg/l). Due to the presence of C‐findings (transfusion dependent anemia, splenomegaly with thrombocytopenia, and malabsorption with weight loss), the criteria for aggressive SM (ASM) were fulfilled. A hilar lymph node biopsy revealed several small lymphocytes next to dense blastoid cell infiltrates of myeloid lineage without MCs consistent with extramedullary hematopoiesis.Together with the neurologist, we hypothesized that ASM and not the natural course of DM2 was causative for the rapid neurological deterioration. Treatment with the KIT‐tyrosine kinase inhibitor midostaurin was initiated. Within three months, the patient gained weight, regained muscle power, dysphagia disappeared, and the PEG could be removed. The blood count normalized, and hilar lymphadenopathy disappeared. Currently, allogeneic hematopoietic cell transplantation is planned because of the poor prognosis of ASM, particularly if KIT‐independent oncogenic driver mutations such as KRAS, ASXL1 and RUNX1 were found.Summary/Conclusion:In summary, awareness of physicians to SM as a possibility in the differential diagnosis of unclear clinical scenarios is the first step to make the diagnosis and offer adequate therapy. Serum tryptase is a simple tool that could draw the attention of physicians to SM.

Clinical and Morphologic Predictors of Outcome in a Multicenter Cohort of ITP Patients Treated with Trombopoietin Analogues

Background: The role of bone marrow response in patients with immune thrombocytopenia (ITP) has gained paramount importance since the last 10 years, with the demonstrations that marrow megakaryocytes (MGK) are unable to properly compensate platelets peripheral destruction. TPO receptor agonists (TPOa), namely romiplostim (ROMI) and eltrombopag (EPAG), by stimulating megakaryopoiesis are able to induce a response in 74% to 94% of cases in clinical trials. However, real world use of these drugs has shown frequent changes in individual dose requirement, the possibility of treatment discontinuation, and their effectiveness outside registered indications; moreover, nothing is known about predictors of response.Aim: To evaluate clinical and morphologic predictors of response in a real world cohort of ITP patients treated with TPOa.Methods: ITP patients treated with EPAG and ROMI from September 2009 to May 2018 at seven Italian Centers were evaluated. Clinical and hematologic parameters including treatment response and marrow characteristics were retrospectively collected.Results: Table 1 shows baseline clinical and morphologic characteristics for the 86 cases enrolled, altogether and divided according to the TPOa used: patients were mainly middle-aged females presenting with severe thrombocytopenia; anti-PLT autoantibodies were positive in 32.6% of cases, and 58.1% of cases presented with bleeding, 22% of grade III-IV. All cases had received 1st line treatment with steroids and 43% at list a 2nd line among those listed in Tab1. Pre-TPOa marrow evalutation showed hypocellularity in 30.2% of cases, reticulinic fibrosis in 33.7%, a polyclonal lymphoid infiltrate in 43% (mostly mixed or T-cell), and reduced MGK in 4.7% of patients. Some dysplastic features were present in about 50% of cases, either dysmegakaryopoiesis (46.5%) or dyserythropoiesis (25.6%). Median time from diagnosis to TPOa was 2.4 years (0.1-28.8). Patients were treated for a median of 1.4 years (0.3-10.8), and ORR at 3 months and 9 months were 75.6% (CR 44.2 and PR 31.4%) and 65.1% (CR 36 and PR 29.1%), respectively. Response rates to EPAG and ROMI were comparable. Regarding predictors of response, bone marrow hypocellularity (40 NR vs 21% ORR, p=0.05) and megakaryocytopenia (33 vs 6%, p=0.06) were significantly more frequent among NRs. Other factors associated with poor response were dyserythropoiesis (58 vs 26%, p=0.04) and erythroid hyperplasia (18 vs 8%, p=0.03), and presence of a T cell infiltrate (66 vs 18.9%, p=0.03). Finally, NRs cases showed significantly lower neutrophil counts at baseline (1.9 vs 2.3x103/mmc in ORR, p=0.01), and had been more frequently exposed to cyclosporine or azathioprine (50 vs 18% in ORR, p=0.01).Fifty-five patients are still on treatment, whereas 31 (20 EPAG/11 ROMI) discontinued because of NR or relapse (17), adverse events or intolerance (2); of note, 12 patients with ORR discontinued the drug because of sustained CR, and 7 of them are still in remission. 14/65(21.5%) responding cases (10 EPAG/4 ROMI) lost the response after a median of 6.2 months (1.8-60) and were variably managed (3 splenectomized, 1 switched from ROMI to EPAG, 1 received danazol, 5 were re-treated with EPAG, and the remaining were managed with steroids and supportive treatment). Median RFS was 2.3 years (0.1-10), longer in patients without megakaryocytopenia (9.9+0.5 vs 4.1+0.6, p=0.06), dyserythropoiesis (mean 9.1+0.5 vs 4.9+0.7, p=0.2), and reticular fibrosis (9.6+0.5 vs 5.5+0.6, p=0.08). During EPAG treatment 7 grade adverse events occurred: 2 grade IV (1 stroke with PLT counts of about 30x103/mmc, and 1 NSTEMI 1 month after EPAG discontinuation for sustained CR), 1 grade III pneumonia, and 4 grade I/II transaminase elevation. No events occurred under ROMI.Conclusions: TPOa use in the real world setting confirms their reported efficacy, the option to switch and/or re-treat with either EPAG or ROMI, and the possibility to discontinue the drugs. The presence of hypocellularity and megakaryocytopenia, along with dysplastic features and of a lymphoid T cell infiltrate are associated with a reduced response to TPOa and a shorter RFS. Pre-treatment bone marrow evaluation may give hints to unravel the physiopathologic mechanisms underlying TPOa refractoriness. [Display omitted] DisclosuresRossi:MUNDIPHARMA: Honoraria; JANNSEN: Other; AMGEN: Other: ADVISORY BOARD; PFIZER: Other: ADVISORY BOARD; BMS: Honoraria; NOVARTIS: Honoraria; ROCHE: Other: Advisory Board; ABBVIE: Other: ADVISORY BOARD; TEVA: Other: ADVISORY BOARD; CELGENE: Other: ADVISORY BOARD; JAZZ: Other: ADVISORY BOARD; SANOFI: Other: ADVISORY BOARD; GILEAD: Other: ADVISORY BOARD; SANDOZ: Honoraria.

Effect of Nitrogen Oxide on the Gums &lt;i&gt;Lamina propria&lt;/i&gt; Structure and Function in the Experimental Gastritis, Duodenitis and Pharmacological Correction

In the conditions of experi mental chronic gastritis and duodenitis reproduction, carried out among Wistar line 24 rats, was investigated effect of the nitrogen oxide stable metabolites content in the gums homogenates on a lamina propria structure and function. Results of our research have been shown, that level of nitrogen oxide stable metabolites in the rats’ gums tissues homogenates with gastritis and duodenitis decreased in three times, compared with a same period at the intact animals, which indicated about depletion of a nitrogen oxide depot at the given disease. It was revealed a significant decrease typical for the protein and glycoprotein content in the animals gums tissues at the experimental group, which indicated about the catabolic processes predominance. Amount of hexosamines in the gums was significantly increased, which was correlated with a morphological picture (gums lamina propria impregnation with the blood plasma proteins), testified about a change in the vascular wall permeability and microcirculation disruption. In the animals from experimental group was reduced a height of gums papillae connective tissue to 27.18±1.86 x 10-6 m against 56.93±2.64 x 10-6 m in the rats from control group. In the gums lamina propria defines phenomenon of the papillary and reticular layer fibrosis. After medicamentous correction, carried out with an antioxidant and the nitrogen oxide donor was observed repairing structure of the gums lamina propria on a background of increasing microvasculature area. It was determined significantly increased protein and glycoprotein content in the gums tissues with increased levels of nitrogen oxide metabolites.

99mTc-IgG-Lung Scintigraphy in the Assessment of Pulmonary Involvement in Interstitial Lung Disease and Its Comparison With Pulmonary Function Tests and High-Resolution Computed Tomography: A Preliminary Study.

Background:The discrimination of inactive inflammatory processes from the active form of the disease is of great importance in the management of interstitial lung disease (ILD).Objectives:The aim of this study was to determine the efficacy of 99mTc-IgG scan for the detection of severity of disease compared to high-resolution computed tomography (HRCT) and pulmonary function test (PFT).Patients and Methods:Eight known cases of ILD including four cases of Mustard gas (MG) intoxication and four patients with ILD of unknown cause were included in this study. A population of six patients without lung disease was considered as the control group. The patients underwent PFT and high-resolution computed tomography, followed by 99mTc-IgG scan. They were followed up for one year. 99mTc-IgG scan assessment of IgG uptake was accomplished both qualitatively (subjectively) and semiquantitatively.Results:All eight ILD patients demonstrated a strong increase in 99mTc-IgG uptake in the lungs, compared to the control patients. The 99mTc-IgG scan scores were higher in the patient group (0.64[95% confidence interval(CI)=0.61-0.69])) than the control group (0.35 (0.35[95% CI=0.28-0.40]), (P<0.05)). In patients, a statistically significant positive correlation was detected between 99mTc-IgG scan and HRCT scores (Spearman’s correlation coefficient = 0.92, P < 0.008). The 99mTc-Human Immunoglobulin (HIG) scores were not significantly correlated with PFT findings (including FVC, FEV1, FEV1/FVC), O2 saturation and age ( P values > 0.05). There were no significant correlations between 99mTc-IgG score and HRCT patterns including ground glass opacity, reticular fibrosis and honeycombing (P value > 0.05).Conclusion:The present results confirmed that 99mTc-IgG scan could be applied to detect the severity of pulmonary involvement, which was well correlated with HRCT findings. This data also showed that the 99mTc-IgG scan might be used as a complement to HRCT in the functional evaluation of the clinical status in ILD; however, further studies are recommended.

A Case of Actinic Keratosis in a Rabbit

Actinic keratosis is well described in humans, dogs, and cats as a precancerous skin growth caused by ultraviolet light–induced DNA damage. This report describes a case of early actinic keratosis in a 6-year-old rabbit (Oryctolagus cuniculus). On dermatological examination, erythema and yellow adherent scales were observed on the external aspect of the pinnae. Mild pruritus was also present on the initial presentation. Histopathology revealed segmental epidermal hyperplasia with loss of polarity in the basal layer. Mild nuclear atypia and marked orthokeratotic hyperkeratosis were present. The superficial dermis had marked reticular fibrosis with thickening of collagen fibrils. Topical treatment with diclofenac resulted in clinical resolution of the disease.

Reactive gliosis of astrocytes and Müller glial cells in retina of POMGnT1-deficient mice

Protein O-linked mannose beta1, 2-N-acetylglucosaminyltransferase 1 (POMGnT1) is an enzyme that catalyzes the transfer of N-acetylglucosamine to O-mannose of glycoproteins. Alpha-dystroglycan, a substrate of POMGnT1, is concentrated around the blood vessels, in the outer plexiform layer (OPL), and in the inner limiting membrane (ILM) of the retina. Mutations of the POMGnT1 gene in humans cause muscle-eye-brain (MEB) disease. Several ocular abnormalities including retinal dysplasia, ERG abnormalities, and retinal detachments have been reported in patients with MEB. We have analyzed the eyes of POMGnT1-deficient mice, generated by standard gene targeting technique, to study the retinal abnormalities. Clinical examination of adult mutant mice revealed a high incidence (81% by 12-months-of-age) of retinal detachments. Sheathing of the retinal vessels and the presence of ectopic fibrous tissues around the optic nerve head were also found. Histological examinations showed focal retinal detachment associated with GFAP immunopositivity. The ILM of the mutant mice was disrupted with ectopic cells near the disruptions. The expression of Dp71, a shorter isoform of dystrophin, was severely reduced in the ILM and around retinal blood vessels of POMGnT1-deficient mice. The expression of Dp427, Dp260, Dp140 were also reduced in the OPL of the mutant mice. Electroretinographic (ERG) analyses showed reduced a- and b-wave amplitudes. Examinations of flat mounts revealed abnormal vascular network associated with highly irregular astrocytic processes. In addition, ER-TR7-positive fibrous tissue was found closely associated with reactive astrocytes especially around the optic nerve head. Our results suggest that altered glycosylation of alpha-DG may be responsible for the reactive gliosis and reticular fibrosis in the retina, and the subsequent developments of retinal dysplasia, abnormal ERGs, and retinal detachment in the mutant mice.

Portale Hypertension unter Azathioprin bei Morbus Crohn - ein häufiges Phänomen?

A 45-year-old man with 18 years history of Crohn's disease who was on treatment with azathioprine (AZA) for the past 48 months was admitted because of haematemesis and melaena. Tests showed a slight elevation of bilirubin and a low platelet count. Endoscopy revealed esophageal and gastric fundus varices. Magnetic resonance imaging (MRI) revealed severe portal vein hypertension with a spleen-kidney convolute of varices. Liver biopsy showed hyperplasia of hepatocytes and a reticular fibrosis, consistent with the diagnosis of nodular regenerative hyperplasia (NRH). AZA treatment was stopped. The fundal varices were treated with endoscopic histoacryl injection. The patient is at present in good health and is followed up in our outpatient department. AZA as a widely used immunosuppressive drug has side effects in about 5 - 10 % of the cases. The risk of hepatotoxicity in patients treated with AZA is often underestimated. Therefore, physicians treating patients with inflammatory bowel disease have to be precocious regarding the increase of hepatic enzymes and pathologic signs in liver imaging in relation of AZA treatment. The latter might refer to NRH which would lead to severe portal vein hypertension.

Myelofibrosis with myeloid metaplasia in a patient with relapsed Hodgkin's lymphoma who underwent autologous hematopoietic stem cell transplantation

Second malignancies after autologous haematopoietic stem-cell transplantation (AHSCT) are well-known long-term complications.We present a case of a 24-year-old male with relapsed Hodgkin lymphoma (HL) with no involvement of his bone marrow who underwent AHSCT. Four years later he developed mild anaemia and a computed tomography showed an enlarged spleen. As his anaemia worsened, a bone marrow was performed. There was no evidence of HL but intense reticular and collagen fibrosis with hypocellularity was detected. Cytogenetic studies could not obtain cells in metaphase in two occasions. PCR for V617F JAK2 mutation was positive. Until now, with 7 years of follow up from his diagnosis of myelofibrosis with myeloid metaplasia (MMM) he did not require specific treatment besides from red cell transfusions when anaemia worsened during a pneumocistis carinii infection.We present this case, because MMM is a infrequent second neoplasm after AHSCT. Revising the literature we could not find any case like this reported previously.

Mast cells in diffuse large B‐cell lymphoma; their role in fibrosis

Mast cells (MCs) are associated with fibrosis in various diseases. MCs comprise two phenotypes: the MC(TC) phenotype contains tryptase and chymase, whereas the MC(T) phenotype contains tryptase. Interleukin (IL)-4 promotes the development of MC(TC) from the MC(T) phenotype. The aim of this study was to determine the relationship between MC phenotypes and fibrosis in diffuse large B-cell lymphoma (DLBCL). We examined the distribution and density of MCs in 50 DLBCL and 20 reactive lymph nodes, and evaluated MC phenotypes and IL-4-expressing cells. To detect MCs, immunohistochemistry for tryptase and chymase was performed. The 50 DLBCLs were histologically divided into three groups: no fibrosis (32 cases), reticular type (eight cases) showing reticular fibrosis, and bundle type (10 cases) showing collagenous bundles. The density of tryptase-positive MCs was higher than that of chymase-positive MCs. The densities of tryptase-positive and chymase-positive MCs in fibrotic areas were significantly higher than those in the cellular areas in the reticular and bundle groups. Double immunostaining revealed that MCs in DLBCL comprised MC(T) and MC(TC) phenotypes. Chymase-positive MCs and T lymphocytes expressed IL-4. Although there were few chymase-positive MCs in reactive lymph nodes, the density of tryptase-positive MCs was not different from that in the 'no fibrosis' group. Tryptase-positive and chymase-positive MCs are associated with fibrosis in DLBCL.

Mast Cells in the Diffuse Large B-Cell Lymphoma; Their Role for Fibrosis.

Mast cells (MCs) play an important role in tissue remodeling in inflammation. According to content of tryptase and chymase, MC is divided into two phenotypes; MCTC phenotype contains tryptase and chymase, while MCT phenotype contains only tryptase. Recent studies have revealed that interleukin-4 (IL-4) promotes the maturation of MCs and the development of MCTC phenotype from MCT phenotype. Although MCs infiltration into diffuse large B-cell lymphoma (DLBCL) has been reported, MC phenotypes infiltrating into lymphomas remain unknown. We examined MC phenotype infiltrating into lymph nodes in 50 DLBCL and 20 reactive lymph nodes, and evaluated their association with fibrosis. We also evaluated IL-4-expressing cells in DLBCL. Reviewing hematoxylin-eosin stain and Azan-Mallory stain, 50 cases with DLBCL were divided into 3 groups; no fibrosis type in 32, reticular type in 8, showing fine reticular fibrosis in focal areas, and bundle type in 10, showing thick collagenous bundle through the parenchyma. Using these formalin-fixed and paraffin-embedded specimens, immunohistochemistry for tryptase and chymase was performed. Furthermore, immunodouble staining methods were performed to detect the MC phenotypes and the cells that express IL-4 in DLBCL, using frozen sections. Tryptase-positive, and chymase-positive MCs were found in all groups of DLBCL and density of tryptase-positive MCs were higher than that of chymase-positive MCs. Densities of trytase-positive, and chymase-positive MCs in fibrotic areas were significantly higher than those in the areas without fibrosis (reticular type; 12.681 ± 11.307 / mm2 vs. 2.082 ± 2.260 / mm2, p = 0.018, bundle type; 22.407 ± 11.989 / mm2 vs. 1.319 ± 1.937 /mm2, p = 0.005, in tryptase-positive MCs, reticular type; 4.758 ± 5.468 / mm2 vs. 0.440 ± 1.164 / mm2, p = 0.028, bundle type; 4.114 ± 5.216 / mm2 vs. 0.220 ± 0.374 / mm2, p = 0.008; in chymase-positive MCs). Numbers of tryptase-positive MCs in reactive lymph nodes were not different from those in no fibrosis type of DLBCL. There were few chymase-positive MCs in reactive lymph nodes. Immunodouble staining revealed that MCs in DLBCL comprised MCT and MCTC phenotypes. Chymase-positive MCs and T-lymphocytes expressed IL-4. These findings suggest that T-lymphcytes play a role in the development of MCTC phenotype from MCT phenotype in DLBCL and that tryptase-positive MCs and chymase-positive MCs are associated with the development of fibrosis in DLBCL.

MR Imaging Findings in Autoimmune Hepatitis: Correlation with Clinical Staging

To retrospectively evaluate the morphologic and enhancement features of the liver on magnetic resonance (MR) images obtained in patients with autoimmune hepatitis (AIH) and to determine if there is a correlation between MR imaging findings and severity of clinical disease as measured with the Mayo end-stage liver disease (MELD) score. This study was compliant with the Health Insurance Portability and Accountability Act and approved by the institutional review board. The need for informed consent was waived. Thirty-two patients (29 female and three male patients; mean age, 44 years; age range, 14-69 years) undergoing treatment for AIH underwent unenhanced and gadolinium-enhanced MR imaging. Two radiologists reviewed all cases independently to determine the presence of patchy or heterogeneous liver enhancement, biliary duct changes, lymphadenopathy, and findings of portal hypertension. Fibrosis was graded as mild, moderate, or severe reticular (corresponding to a grading scale of 1-3) or as confluent. Agreement between radiologists was assessed by using kappa coefficients. Mean MELD scores were compared across fibrosis categories by using the Kruskal-Wallis analysis of variance. Of the 32 patients, two (6%) had no imaging findings of cirrhosis. Thirty patients (94%) had reticular fibrosis with a mean grade of 1.8. Six patients had confluent fibrosis, and all six had associated reticular fibrosis. Mild intrahepatic biliary duct dilatation involving the right and left lobes was observed in four patients (12%). Lymphadenopathy was observed in 12% of patients. None of the patients had hepatocellular carcinoma. There was no significant overall association between fibrosis grade and MELD score (P = .36). Although fibrosis is a common feature in AIH and is often moderate to severe, no significant correlation between fibrosis grade and MELD score was found.

Prevention of bleomycin-induced lung fibrosis by aerosolization of heparin or urokinase in rabbits.

Bleomycin is a well known fibrogenic agent, provoking an initial adult respiratory distress syndrome-like injury with subsequent strong fibroproliferative response. Severe abnormalities of the alveolar surfactant system, which may be linked to the appearance of alveolar fibrin deposition, have been implicated in the pathogenetic sequence of events. Using a model of standardized aerosol delivery of 1.8 U bleomycin/kg body weight in rabbits, we investigated the influence of repetitive nebulization of heparin or urokinase-type plasminogen activator (u-PA) on the development of lung fibrosis. In an "early" (Days 2-12 postbleomycin) or "late" (Days 14-24 post-bleomycin) treatment protocol, approximately 3,500 U heparin or approximately 6,500 U u-PA was delivered to the bronchoalveolar space. Within four weeks, the bleomycin challenge provoked severe pulmonary fibrosis with reduction of lung compliance, marked increase in soluble collagen (bronchoalveolar lavage fluid) and hydroxyproline content (lung tissue), a typical reticular fibrosis pattern on high-resolution computed tomography, and typical histologic findings. Therapeutic intervention resulted in a far-reaching normalization of compliance, suppression of soluble collagen and hydroxyproline accumulation, and virtual abrogation of the computed tomography scan and histologic features of lung fibrosis, with most prominent effects seen in the early heparin and late u-PA administration. No bleeding complications occurred. These findings strongly support the concept that alveolar fibrin generation is an important event in the development of postbleomycin lung fibrosis. "Compartmentalized" anticoagulation and/or fibrinolysis via inhalational deposition of interventional agents in the alveolar compartment may thus offer a new therapeutic strategy for prevention of fibrosis.

Bone marrow biopsy in adult acute lymphoblastic leukemia: morphological characteristics and contribution to the study of prognostic factors

Bone marrow (BM) sections were examined in 128 untreated adult patients with newly diagnosed acute lymphoblastic leukemia (ALL), seen in our institution over a 19-year period. BM biopsy was performed in order to assess the incidence, degree and prognostic significance of histological data of the disease. BM features studied were reticular fibrosis, total cellularity, residual hematopoiesis, mitotic activity, and blastic infiltration. T-cell lineage ALL were diagnosed in 23% of the cases, while B-cell lineage ALL represented 70% of the cases. There were 7% of non-T-non-B-cell lineage ALL. The percentage of BM leukemic cells was related to cellularity ( P=0.02), while it was related to the disappearance of normal cell lines ( P<0.0001). BM cellularity was related to the percentage of circulating leukemic cells at diagnosis ( P=0.006). Residual hematopoiesis was related to a higher initial granulocyte count ( P=0.04) and lower percentage of circulating blasts ( P=0.04). The degree of fibrosis was inversely related to that of BM cellularity ( P=0.04). All patients, but four, received standard ALL induction chemotherapy according to different successive protocols. In this whole cohort of patients, complete remission (CR) rate was 78%. Median disease-free survival (DFS) and median overall survival (OS) were 13.7 months and 20.2 months, respectively. In univariate analysis, CR rate was positively affected by mitotic activity ( P=0.01) and residual hematopoiesis ( P=0.008). OS was positively influenced by a higher leukemic cell mitotic activity ( P=0.03) and the persistence of more than two residual normal cell lines in BM ( P=0.04). Patients presenting with both of those characteristics had better outcome than patients who did not, as well as, in terms of CR ( P=0.03), or DFS ( P=0.002), or OS ( P=0.003). T-cell lineage ALL and L3 ALL did not significantly influence those results. Our findings did not confirm that among marrow features, reticular fibrosis has any prognostic value. A multivariate analysis of both clinical and histological data was performed to test their prognostic relevance. In a model including age, immunophenotype, Philadelphia chromosome status, mitotic index, and level of normal residual hematopoiesis, the only significant predictor of CR achievement were the persistence of normal residual hematopoietic cell lines ( P=0.01) and the mitotic activity of leukemic cells ( P=0.002). Philadelphia chromosome status ( P=0.03) and age ( P<0.0001) were of prognostic value, respectively for DFS and OS. We conclude that some characteristics of BM biopsy afford not only descriptive but also prognostic information for predicting the outcome. The persistence of normal residual hematopoiesis and intense leukemic cells mitotic activity were both factors of favorable outcome, while BM fibrosis did not display any prognostic value.

Cirrhosis: spectrum of findings on unenhanced and dynamic gadolinium-enhanced MR imaging.

The appearance of the cirrhotic liver on computed tomography can be difficult to evaluate and can frustrate the radiologist distinguishing benign from malignant lesions. Hepatic edema, fibrosis, atrophy, and vascular abnormalities are common in the cirrhotic liver and produce derangements in morphology, attenuation, and perfusion, limiting the accurate characterization of hepatic masses. With the development of fast magnetic resonance (MR) sequences and dynamic postgadolinium-enhanced imaging, most hepatic lesions with uncertain etiology on computed tomography can be accurately characterized on MR imaging. We describe MR imaging techniques useful for imaging cirrhosis and its complications. We also illustrate the spectrum of findings in the cirrhotic liver on dynamic gadolinium-enhanced MR imaging, including reticular and confluent fibrosis, fatty infiltration, hemochromatosis, regenerating nodules, dysplastic nodules, hepatocellular carcinoma, and sequela of portal hypertension.

Better-surviving liver grafts by the injection of anti-CD2 antibody: the important roles of host CD8+ and CD2+CD28+ T cells in chronic graft rejection and beta type platelet-derived growth factor receptor (PDGFR-beta) expression on apoptotic liver grafts.

Syngeneic liver grafts were implanted in the livers of 22 LEW/Sea strain rats. To prolong the graft survival, anti-CD2 monoclonal antibody (MAb) or anti beta type platelet-derived growth factor receptor (PDGFR-beta) antibody (Ab) was injected, or splenectomy was performed in the rats which were then followed until 10 to 11 weeks posttransplantation. The 22 rats with chronic graft rejection showed increased CD8a-like antigen (probably Fas ligand) on the peripheral blood T cells. All the liver grafts had both necrosis and apoptosis. The liver graft apoptosis was indicated by histopathological abnormalities, and by DNA strand breaks and hemosiderin depositions in the cytoplasm. PDGFR-beta expression in the apoptotic liver graft was demonstrated immunohistochemically. Among the 17 rats injected with anti-CD2 MAb, CD2 signaling on host T cells was effectively suppressed by the injection of anti-CD2 MAb in 4 rats with better-surviving liver grafts. In these 4 rats, CD28 antigen on thymic lymphocytes was down-modulated and high numbers (136-233-positive cells per lobe) of the epithelial reticular cells with apoptotic lymphocytes were counted. Anti-PDGFR-beta Ab caused high pulmonary secretions of growth factors and reticular fibrosis in the lungs of 5 rats injected with the Ab. Anti-PDGFR-beta Ab injection reduced the host cell apoptosis in the lung and thymus, but did not prolong the survival of liver grafts. In the 9 rats with both splenectomy and anti-CD2 MAb injection, pulmonary apoptosis was induced with the 6-16% reductions of CD4+ lymphocytes. Prolonged graft survival was observed in only one of the 9 rats. Anti-CD2 MAb was effective for prolonging the liver graft survival with suppressed CD28 antigen, but anti-PDGFR-beta Ab and splenectomy were not.

Bone Marrow Findings in Acquired Immunodeficiency Syndrome (AIDS)

Bone marrow aspirates and biopsies from 35 AIDS/AIDS-related complex patients, consisting primarily of intravenous drug abusers, were studied. The most common findings included hypercellularity (86%), plasmacytosis (63%), reticular fibrosis (50%), and lymphocytosis (37%) occasionally admixed with histiocytes. Granulocytic hyperplasia was present in 27 patients (77%). Erythrocytic hypoplasia was observed in 15 patients (43%). Megaloblastic changes of intermediate form were seen in two cases and serous fat atrophy was noted in another three patients. One M. tuberculosis granuloma, a foreign body granuloma and two granulomas of undetermined etiology were seen, each in separate patients. A previously unreported focal vascular proliferation was seen in one case. The majority of cases showed increased stainable iron. Some of our findings are at variance with previous reports. This may reflect differences in patient population, geographic distribution, risk factors and epidemiologic mode in our cases.