Cardiosphere-Derived Cells Attenuate Inflammation, Preserve Systolic Function, and Prevent Adverse Remodeling in Rat Hearts With Experimental Autoimmune Myocarditis.

BACKGROUND: Cardiosphere-derived cells (CDCs) have yielded promising efficacy signals in early-phase clinical trials of ischemic and nonischemic cardiomyopathy. The potential efficacy of CDCs in acute myocarditis, an inflammatory cardiomyopathy without effective therapy, remains unexplored. Given that CDCs produce regenerative, cardioprotective, anti-inflammatory, and anti-fibrotic effects (all of which could be beneficial in acute myocarditis), we investigated the efficacy of intracoronary delivery of CDCs in a rat model of experimental autoimmune myocarditis. METHODS: Lewis rats underwent induction of experimental autoimmune myocarditis by subcutaneous footpad injection of purified porcine cardiac myosin supplemented with Mycobacterium tuberculosis on days 1 and 7. On day 10, rats were randomly assigned to receive global intracoronary delivery of 500 000 CDCs or vehicle. Global intracoronary delivery was performed by injection of cells or vehicle into the left ventricular (LV) cavity during transient occlusion of the aortic root. Rats were euthanized 18 days after infusion. Cardiac volumes and systolic function were assessed by serial echocardiography, performed on days 1, 10, and 28. Myocardial inflammation, T-cell infiltration, and cardiac fibrosis were evaluated by histology. RESULTS: Experimental autoimmune myocarditis was successfully induced in 14/14 rats that completed follow-up. Left ventricular ejection fraction (LVEF) and volumes were comparable on days 1 and 10 between groups. CDC infusion resulted in increased LVEF (81.5% ± 3% vs 65.4% ± 8%, P < .001) and decreased LV end-systolic volume (43 ± 15 vs 100 ± 24 µL, P < .001) compared to placebo administration at 18 days post-infusion. Cardiosphere-derived cell infusion decreased myocardial inflammation (7.4% ± 7% vs 20.7% ± 4% of myocardium, P = .007), cardiac fibrosis (16.6% ± 13% vs 38.1% ± 3% of myocardium, P = .008), and myocardial T-cell infiltration (30.4 ± 29 vs 125.8 ± 49 cells per field, P = .005) at 18 days post-infusion compared to placebo administration. CONCLUSION: Intracoronary delivery of CDCs attenuates myocardial inflammation, T-cell infiltration, and fibrosis while preventing myocarditis-induced systolic dysfunction and adverse remodeling in rats with experimental autoimmune myocarditis.

Treatment of Experimental Candida Sepsis with a Janus Kinase Inhibitor Controls Inflammation and Prolongs Survival.

Janus kinases (JAK) are intracellular tyrosine kinases that transduce cytokine-mediated signals to the nucleus, promoting gene expression. Cytokines play a major role in microbial sepsis, which is often associated with uncontrolled inflammation leading to death. JAK inhibitors have been used for the treatment of several autoimmune diseases by modulating immune response, but they have never been tested against microbial sepsis. Ruxolitinib is a small-molecule inhibitor of JAK1/2 proteins, which are involved in the downstream signaling pathway of the vast majority of proinflammatory and anti-inflammatory cytokines. We therefore studied the effect of ruxolitinib in a mouse model of sepsis due to Candida albicans. When ruxolitinib therapy (50 mg/kg [of body weight]/day) was started 1 day before infection, the median survival time was reduced by 3 days, the fungal loads in all organs were higher, the inflammation was significantly less, and serum tumor necrosis factor alpha (TNF-α) and interleukin 10 (IL-10) levels and IL-10/TNF-α ratios were higher than in controls. When ruxolitinib therapy (50 to 1.5 mg/kg/day) was started 1 day after infection, an inverted-U relationship was found, with 6.25 mg/kg/day prolonging median survival time by 6 days, resulting in similar fungal loads, less inflammation, and similar cytokine levels but higher IL-10/TNF-α ratios than the controls. The optimal dose of ruxolitinib controlled infection and prolonged survival with less inflammation than in control animals. Administration of JAK inhibitors may be a promising therapeutic adjunct that needs further investigation.

Endosonographic features of unicentric Castleman Disease.

BACKGROUND: Castleman disease (CD) is a rare lymphoproliferative disorder most frequently occurring in the mediastinum. Peripancreatic forms are less frequent. Few cases of endoscopic ultrasonography-fine-needle aspiration (EUS-FNA) findings of this lesion have been reported, where no real-time tissue elastography (RTTE) has been described in the literature to our knowledge. METHODS: We describe the endosonographic, elastographic, cytologic and immunocytochemistry findings in two cases of unicentric CD of the hyaline vascular variant. RESULTS: Two females, aged 41 and 34 year were referred to our hospital for further EUS evaluation of a peripancreatic mass found incidentally on computed tomography. EUS examination revealed around, well-demarcated, uniformly hypoechoic mass measuring 52 and 23 mm respectively, with smaller adjacent hypoechoic lymph nodes. Doppler examination revealed intense peripheral vascularity, together with prominent penetrating feeding vessels entering a distinct hilum. RTTE revealed a relatively homogenous soft elastographic pattern. EUS-FNA provided smears with clusters of lymphocytes in a hemorrhagic background. Cell block preparation showed immature lymphocytes surrounding lymphocyte-poor centers with vascular proliferation. Immunohistochemical staining of the cell block sections showed CD45-leukocyte common antigen, CD20, CD23, CD79a, Bcl-2 and CD5 positivity in small lymphocytes. Cytology was suggestive of non-Hodgkin's lymphoma. Surgical excision was performed in both cases and histopathology was consistent with CD of the hyaline vascular type. CONCLUSION: The echo features of a solitary hypoechoic homogenous well-demarcated mass with prominent vasculature and increased elasticity should raise the possibility of unicentric CD. EUS-FNA usually cannot make a definitive distinction from certain kinds of lymphoma.

A Case of Distal Epithelioid Sarcoma of the Thumb Expressing Podoplanin, TLE1 and Ca 125.

Distal epithelioid sarcoma is a rare and slowly growing tumor that usually develops in the upper extremities of young adults. Neoplastic cells have both spindle and epithelioid appearance and are characterized by the loss of the nuclear protein SMARCB1/INI1. We present the case of a distal epithelioid sarcoma arising in the thumb of a 14-year-old girl, which immunohistochemically was characterized by the loss of SMARCB1/INI1 protein as well as the expression of podoplanin (D2-40), TLE1, Glut1, and Ca 125; plus, we highlight the differential diagnosis of epithelioid sarcoma from its histological mimics.

Low-grade mucosa-associated lymphoid tissue lymphoma: a retrospective analysis of 97 patients by the Hellenic Cooperative Oncology Group (HeCOG).

BACKGROUND: The aim was to examine characteristics and treatment results of patients with mucosa-associated lymphoid tissue (MALT) non-Hodgkin's lymphomas. PATIENTS AND METHODS: Epidemiological and clinical features of 97 patients with MALT lymphoma from the Hellenic Cooperative Oncology Group registry were analysed retrospectively for their prognostic significance in progression-free survival (PFS) and overall survival (OS). Comparisons were made between patients with gastric and nongastric sites of primary lymphoma and between different therapeutic modalities. RESULTS: Sixty-five patients presented with gastric and 32 with nongastric lymphomas. The most frequent locations of nongastric lymphomas were the bowel, lung and parotid. Gastric lymphomas occurred more frequently in males and younger patients compared with nongastric lymphomas. Seventy-four per cent of patients had early (Ann Arbor stages I-II) and 26% had advanced (stages III-IV) disease. The median PFS for the entire population was 44 months. At 5 years, 47% of patients were progression free and the OS rate was 80%. The most reliable prognostic factor for PFS and OS was the Ann Arbor stage; 5-year PFS was 67% versus 13% and 5-year OS 91% versus 51% for patients with early versus advanced disease, respectively (P < 0.001). Of the patients treated with chemotherapy only, 87% achieved an objective response and 71% complete response. Surgery did not offer survival benefit compared with chemotherapy in localised gastric lymphoma. CONCLUSION: MALT lymphomas represent a distinct disease entity with widespread extranodal origin, indolent clinical course and high chemosensitivity. Ann Arbor stage was the most reliable prognostic and predictive factor.

Eosinophilic granuloma masquerading as aggressive periodontitis.

BACKGROUND: Eosinophilic granuloma (EG) is the mildest and mainly localized form of the clinicopathologic spectrum of Langerhans' cell histiocytosis. It is a destructive osseous lesion characterized by a vast number of eosinophils and histiocytes. The etiology remains unknown. In this paper, a case of EG is presented that was initially diagnosed and treated as aggressive periodontitis (AP). METHODS: Despite treatment procedures, the EG continued to expand very quickly, destroying the lingual cortical bone and the neighboring soft tissues and exhibiting periosteal reaction. Diagnosis of EG was established on the basis of histopathologic and immunohistochemical evaluation. Moreover, certain manifestations in the skeletal and respiratory system were observed. RESULTS: Surgical curettage of the lesions was effective; however, corticosteroids and low-dose radiation were used as adjunctive therapy. CONCLUSION: The rapid progress of eosinophilic granuloma, the diagnostic problems, and the consequences of late diagnosis and treatment are discussed.

Malignant triton tumour of the anterior mediastinum as incidental finding.

A rare case of malignant peripheral nerve sheath tumour with rhabdomyoblastic differentiation (malignant triton tumour) of the anterior mediastinum in a 30-year-old male is reported. The tumour was an incidental finding during the diagnostic work-up following a motor vehicle accident. The patient underwent median sternotomy with a tumour resection performed. Local relapse was suspected one month later, as per the chest CT-scan, and post-operative chemoradiation was applied, which produced a response. Twelve months later the patient is doing well while radiological findings remain invariable. Localization of a triton tumour in the anterior mediastinum is extremely rare, adjuvant treatment is necessary, recurrence frequently occurs and the prognosis is dismal.

Non-Hodgkin's lymphomas in Greece according to the WHO classification of lymphoid neoplasms. A retrospective analysis of 810 cases.

The purpose of this retrospective study, the largest unselected series in our country, was to illustrate the clinicopathological features of non-Hodgkin's lymphoma (NHL) classified according to the World Health Organization (WHO) classification of lymphoid neoplasms. A retrospective analysis was conducted and clinical features of histological subtypes were established in 810 patients (age > or = 15 years) with NHL who were treated at 8 major centers representative of Greece. There were 435 males and 375 females 95% of them aged >30 years. B symptoms were present in 34% of the patients, while 45.3% had stages I-II and 54.6% had stages III-IV. LDH was increased in 37% of the patients. B cell lymphomas formed 88% of the cases whereas T cell lymphomas formed 12% of the total. Indolent lymphomas accounted for 31.1%, aggressive ones for 66.7% and very aggressive ones for 2.4% of all NHLs. Among indolent lymphomas extranodal ones (MALT B cell lymphoma) were the most common subset while follicular lymphoma grade I and II and small lymphocytic ones presented with equal frequency. Among the aggressive lymphomas diffuse large cell lymphoma (DLCL) was the most common subtype; this entity along with large-cell immunoblastic lymphomas accounted for 45.2% of all B cell lymphomas. Among the T cell lymphomas, peripheral T cell lymphomas and anaplastic large cell lymphomas of the T/null-cell type were the most common subtypes. The most common extranodal presentation was the gastrointestinal tract (GI). Next in frequency were primary extranodal NHL of the head and neck region. MALT B cell lymphomas were found in almost half of the patients with GI tract NHL, whereas in all other extranodal places DLCL was the predominant histological subtype. The median survival for indolent and aggressive NHL was 123.5 and 55.5 months, respectively. This is the first report of a large series of malignant lymphomas in Greece using the WHO classification. It appears that there are no significant differences between NHL in Greece and other large series as far as clinical and extranodal presentation is concerned. The frequency of follicular lymphoma in the current study is comparable to that reported from Asian countries and mainland Europe, but lower than that of US and Northern European series. There were no important differences in the incidence of the remaining histological subtypes between Greece and other European countries.

A reappraisal of the utility of somatostatin receptor scintigraphy in patients with ectopic adrenocorticotropin Cushing's syndrome.

Ectopic ACTH hypersecretion is a rare cause of Cushing's syndrome. Bronchial carcinoids are the most common neoplasms causing the occult ectopic ACTH syndrome (EAS). Localization of these tumors is often difficult. The diagnostic utility of somatostatin receptor scintigraphy (SRS) in EAS has been studied in a limited number of patients with conflicting results. Herein we report our experience with 12 consecutive cases. Histological confirmation was obtained in nine patients, the majority being bronchial carcinoids. Among the seven patients with histologically confirmed bronchial carcinoids, SRS was performed in six patients. In three patients SRS correctly localized a bronchial carcinoid tumor at presentation. In the remaining three it became positive after 8, 22, and 27 months during follow-up. In two patients SRS was positive without any finding in the corresponding conventional imaging study. In two patients positive computed tomography/magnetic resonance imaging preceded SRS localization. There was no false positive SRS. Among three patients with highly suspected EAS, SRS was positive in one. Both patients with EAS due to medullary thyroid carcinoma had focal positive uptake. In summary, in this study a substantial number of patients had positive tumor localization by SRS. Therefore, SRS is a useful tool in the evaluation of patients with EAS.

Inflammatory infiltrate of chronic periradicular lesions: an immunohistochemical study.

AIM: To determine the cellular profile of human chronic periradicular lesions using immunohistochemical methods in order to study the differences in the cell infiltrate of periradicular granulomas and cysts. METHODOLOGY: The study population consisted of 45 individuals without any systemic disease. Biopsies were obtained during periradicular surgery. Paraffin-embedded sections were stained by the avidin-biotin complex method (ABC), whilst cryostat tissue sections were stained using the alkaline phosphatase antialkaline phosphatase assay (APAAP). These methods are highly valid and sensitive using a panel of specific monoclonal antibodies: CD4, CD8, CD3, CD10, HLADR, CD20, CD45RO, CD68 and CD57. The 45 specimens were characterized by the use of both techniques. RESULTS: The 45 specimens were histologically diagnosed as: 25 periradicular granulomas, 17 periradicular cysts and 3 scar tissues. No statistically significant differences were detected in the inflammatory infiltrate between periradicular granulomas and cysts. Observation of the sections showed that the majority of inflammatory cells consisted of T and B lymphocytes and macrophages. T and B lymphocytes were equally distributed in 60% of the cases. The T4/T8 ratio ranged approximately from 1 to 3 and greater, being consistent with inflammation of periradicular tissues. The final differentiation of B lymphocytes to plasma cells was also detected, whilst natural killer (NK) cells were found in only 10 cases (22%). Moreover, antigen presenting cells and T suppressor/cytotoxic cells were found to be associated with both pre-existing and newly formed epithelium. CONCLUSIONS: Periradicular granulomas and cysts represent two different stages in the development of chronic periradicular pathosis as a normal result of the process of immune reactions that cannot be inhibited.

Multiple cervical and intrathoracic plexoid neurofibromas. Case report.

A 29-year-old male with known von Recklinghausen's disease is presented. The main symptom of the patient was paroxysmal episodes of pain and numbness in the right upper hand for the last 10 years. Cervical and mediastial magnetic resonance imaging (MRI) revealed 3 large tumors originating from the right vagus nerve and another of the same origin contralaterally. Surgical resection of the masses in the right hemithorax was performed via right posterolateral thoracotomy. The postoperative course was uneventful and symptoms recessed. Plexoid neurofibromas were diagnosed at histological examination. The mass in the left hemithorax is under surveillance according to the patient's preference. The clinical, radiological, surgical, and histopathological features of this rare case are discussed.

Extranodal cytotoxic T-cell lymphoma in a patient with X-linked agammaglobulinaemia.

This report documents the occurrence of an extranodal cytotoxic peripheral T-cell lymphoma (PTCL) in a patient with X-linked agammaglobulinaemia (XLA). The diagnosis was based on the immunohistochemical detection of T-cell antigens and of the cytotoxic proteins TIA1 and Granzyme B in the tumour cells. This report provides further evidence that cytotoxic lymphomas are part of the differential diagnosis of neoplasia in patients with immunodeficiencies.

T-cell-rich B-cell lymphoma. Analysis of clinical features, response to treatment, survival and comparison with diffuse large B-cell lymphoma.

OBJECTIVES: Clinical features, response to treatment and survival of T-cell-rich B-cell lymphoma (TCRBCL) patients were compared to those of a similar group of patients with diffuse large B-cell lymphoma (DLBCL). METHODS: Between 1992 and 1999, 10 patients with a diagnosis of TCRBCL were treated in our department. Over the same 7-year period, a group of 65 patients with DLBCL were diagnosed in the same department. Both groups of patients were treated with the same anthracycline-based chemotherapy. RESULTS: A significantly higher percentage of patients with TCRBCL presented with B-symptoms, elevated LDH, bone marrow infiltration and disseminated extranodal involvement compared to patients with DLBCL. TCRBCL patients responded poorly to combination chemotherapy, since only 3 of them achieved complete remission (33%) compared to 48 (75%) patients with DLBCL. All patients with TCRBCL who achieved complete response relapsed within the first 2 years while 65% of patients with DLBCL survive disease free for a median follow-up period of 4 years. The median overall survival for DLBCL patients has not been reached yet, while it was 18 months for TCRBCL patients. CONCLUSIONS: Although the number of patients in our study is small, it seems that patients with TCRBCL present with advanced disease, respond poorly to chemotherapy and display a short disease-free and overall survival compared to patients with DLBCL.

Immunohistochemical expression of p53, p21/waf1, rb, p16, cyclin D1, p27, Ki67, cyclin A, cyclin B1, bcl2, bax and bak proteins and apoptotic index in normal thymus.

The immunohistochemical expression of p53, p21, Rb, p16, cyclin D1, Ki67, cyclin A, cyclin B1, p27, bcl2, bax, and bak proteins and the apoptotic index (Al) were investigated in 20 normal thymuses (8 adults, 3 adolescents, 5 infants and 4 newborns). The expressions of Rb, Ki67, cyclin A and cyclin B1 were overlapping, being high in the cortex with a tendency for decreased expression toward the medulla. Apoptotic cells were mainly detected in the cortex and the corticomedullary junction, rarely being present in Hassall's corpuscles. The mean values of Ki67, cyclin A, and cyclin B1 expression in thymuses were 77.2%, 32.2% and 21.4% (newborns), 62.4%, 33.7% and 18.5% (infants), 56.9%, 23.4% and 18.9% (adolescents) and 38.7%, 21.7% and 14.6% (adults), respectively. The mean values of AI in thymuses from newborns, infants, adolescents and adults were 1.4%, 2.9%, 2.7% and 3.8%, respectively. This decrease in proliferation and increase in apoptosis may account for the process of thymic involution. P16 expression was widespread with most of Hassall's corpuscles being p16-positive. P16-positive cells and Hassall's corpuscles increased with the increase in age, in keeping with the suggested role of p16 in cellular senescence. P27 expression was undetectable in subcapsular thymocytes with a tendency for increased expression toward the medulla. The expressions of Ki67, cyclin A and cyclin B1 were inversly related with that of p27, consistent with previous evidence that p27 concentration is reduced when the cell-cycle progresses. P21 and much less frequently p53 proteins were mainly detected in a part of the subcapsular cortical epithelial cells. These findings suggest that a) in thymocytes, the apoptotic pathway is mostly p53-independent and the function of p21 as a negative regulator of the cell cycle must be redundant to other negative regulators, such as p16 and p27 which were abundantly detected in thymocytes and b) in some thymic epithelial cells, the p21 expression may be induced by p53, but in most of them seems to be p53-independent. Most of Hassall's corpuscles were p21-positive, consistent with previous evidence that these structures represent end stages of maturation of thymic medullary epithelium and that p21 protein is involved in the process of terminal differentiation. Cyclin D1 positivity was found in some macrophages. Bcl2 expression was mainly seen in medullary thymocytes, reflecting the surviving thymocytes in this region. The expressions of Bax and bak were more widespread in both the medulla and cortex, suggesting that these proteins play a broader role than bcl2 in the regulation of thymic apoptosis.

Multiple myeloma as the first manifestation of acquired immunodeficiency syndrome: a case report and review of the literature.

Various hematologic malignancies and solid tumors are increasingly diagnosed in patients with human immunodeficiency virus (HIV) infection and may be the presenting manifestation of acquired immunodeficiency syndrome (AIDS). Multiple myeloma, however, has never been reported as the presenting manifestation of AIDS. We report on a 34-year-old man who presented with back pain, paresthesias, paraparesis, vertebral bony disease, and an associated soft tissue mass. Biopsy of the mass revealed immature plasmacytes with very faint cytoplasmic expression of kappa light chains. Bone marrow biopsy revealed 25% infiltration with poorly characterized malignant cells and 15% polyclonal plasma cells. Immunofixation of serum and urine was positive for IgG kappa and kappa light chains, respectively. A bone survey revealed lesions in the skull, left femur bone, and the pelvis. The diagnosis of an anaplastic myeloma was made. Because of the poorly characterized nature of the malignant cells and the difficulties in immunophenotyping, serologic evaluation for HIV was undertaken and was positive. The concept of myeloma as an opportunistic neoplasm defining AIDS was considered. We discuss this view and recommend that patients with multiple myeloma with poorly characterized myeloma cells as well as difficulties in immunophenotyping should undergo testing for HIV infection.

Aspergillus bronchitis causing atelectasis and acute respiratory failure in an immunocompromised patient.

Aspergillus tracheobronchitis is an uncommon clinical form of invasive aspergillosis with fungal infection limited entirely or predominantly to the tracheobronchial tree. We report a case of Aspergillus fumigatus bronchitis, diagnosed by fiberoptic bronchoscopy, with fungal growth completely occluding the left main bronchus leading to lung collapse and acute respiratory failure in a 60-year-old male with erythroleukemia and profound granulocytopenia.