Molecular impact of selective NFKB1 and NFKB2 signaling on DLBCL phenotype.

Diffuse large B-cell lymphoma (DLBCL) has been categorized into two molecular subtypes that have prognostic significance, namely germinal center B-cell like (GCB) and activated B-cell like (ABC). Although ABC-DLBCL has been associated with NF-κB activation, the relationships between activation of specific NF-κB signals and DLBCL phenotype remain unclear. Application of novel gene expression classifiers identified two new DLBCL categories characterized by selective p100 (NF-κB2) and p105 (NF-κB1) signaling. Interestingly, our molecular studies showed that p105 signaling is predominantly associated with GCB subtype and histone mutations. Conversely, most tumors with p100 signaling displayed ABC phenotype and harbored ABC-associated mutations in genes such as MYD88 and PIM1. In vitro, MYD88 L265P mutation promoted p100 signaling through TAK1/IKKα and GSK3/Fbxw7a pathways, suggesting a novel role for this protein as an upstream regulator of p100. p100 signaling was engaged during activation of normal B cells, suggesting p100's role in ABC phenotype development. Additionally, silencing p100 in ABC-DLBCL cells resulted in a GCB-like phenotype, with suppression of Blimp, IRF4 and XBP1 and upregulation of BCL6, whereas introduction of p52 or p100 into GC cells resulted in differentiation toward an ABC-like phenotype. Together, these findings identify specific roles for p100 and p105 signaling in defining DLBCL molecular subtypes and posit MYD88/p100 signaling as a regulator for B-cell activation.

Acinic cell carcinoma-papillary cystic variant. Pitfalls of fine needle aspiration diagnosis: study of five cases and review of literature.

OBJECTIVES: Acinic cell carcinoma (ACC) accounts for 12-17% of primary salivary gland carcinomas and 3.4% of all salivary gland neoplasms. ACC-papillary cystic variant (PCV) is a distinct subtype with clear-cut and well-defined morphological features as revealed in tissue sections, but it is more difficult to diagnose accurately on fine needle aspiration (FNA). The aim of this article was to discuss the causes of the erroneous interpretation as well as to draw attention of practicing pathologists to this rare and unique variant of ACC. METHODS: A computerized search of surgical and cytopathology files identified five diagnoses of ACC-PCV that were preceded by an FNA performed in-house with available slides for review. Cytological features were compared to histomorphological features of excisional surgical pathology specimens. RESULTS: Cytomorphological findings from these ACC-PCV cases have varied features that can be broadly divided in two major subtypes: hypocellular cystic specimens containing histiocyte-like vacuolated cells (two cases) and more cellular specimens containing papillary clusters of cells with a polymorphous appearance including granular cells, vacuolated cells and nondescript small cuboidal cells (three cases). CONCLUSIONS: Hypocellular, cyst-like specimens pose a diagnostic problem when using FNA, as they can easily be misinterpreted as a benign cyst of the salivary gland. Our review of cases found certain 'red flags' that should prompt pathologists to further investigate the true acinic origin of hypocellular cystic specimens. On close morphological examination, these specimens revealed the presence of tight cellular clusters, distinct cytoplasmic borders, larger nuclei with distinct nucleoli and binucleated cells.

Cervical schistosomiasis, human papilloma virus (HPV), and human immunodeficiency virus (HIV): a dangerous coexistence or coincidence?

BACKGROUND: Female genitourinary schistosomiasis (FGS) is widespread in endemic areas causing significant morbidity and mortality. Recent data suggest that FGS of the cervix not only is considered a risk factor for contracting different sexually transmitted diseases (STD), but also plays a significant role in modifying the natural history and immunological response to those infections, in particular HIV and HPV. CASE REPORT: A 32-year-old female from Zambia, who was recently diagnosed with HIV and high-grade dysplasia with koilocytosis on cervical Pap smear, underwent cervical conization which confirmed moderate cervical dysplasia and also revealed the presence of viable and nonviable schistosoma eggs in cervical stroma. Four different HPV types were isolated by PCR, including one "low-risk" (type 6) and three "high-risk" types (types 45,56, and 58). CONCLUSION: The presence of HPV, HIV infection, and cervical schistosomiasis in our patient is likely more than coexistence of multiple agents in the same milieu as cervical schistosomiasis increase susceptibility for other STDs including HIV and HPV. Therefore, in patients with schistosomiasis, immediate treatment for schistosomiasis and additional testing for HIV and HPV is warranted.

Norepinephrine enhances adhesion of HIV-1-infected leukocytes to cardiac microvascular endothelial cells.

Recent reports have indicated that norepinephrine (NE) enhances HIV replication in infected monocytes and promotes increased expression of select matrix metalloproteinases associated with dilated cardiomyopathy (DCM) in vitro in co-cultures of HIV-infected leukocytes and human cardiac microvascular endothelial cells (HMVEC-C). The influence of NE on HIV infection and leukocyte-endothelial interactions suggests a pathogenic role in AIDS-related cardiovascular disease. This study examined the effects of norepinephrine (NE) and HIV-1 infection on leukocyte adhesion to HMVEC-C. Both flow and static conditions were examined and the expression of selected adhesion molecules and cytokines were monitored in parallel. NE pretreatment resulted in a detectable, dose-dependent increase of leukocyte-endothelial adhesion (LEA) with both HIV-1-infected and -uninfected peripheral blood mononuclear cells (PBMCs) relative to media controls after 48 hr in co-culture with HMVEC-C in vitro. However, the combination of NE plus HIV infection resulted in a significant (P < 0.0001) 18-fold increase in LEA over uninfected media controls. Increased levels in both cell-associated and -soluble ICAM-1 and E-Selectin but not VCAM-1 correlated with increased LEA and with HIV-1 infection or NE pretreatment. Blocking antibodies specific for ICAM-1 or E-Selectin inhibited HIV-NE-induced LEA. These data suggest a model in which NE primes HIV-1-infected leukocytes for enhanced adhesion and localization in HMVEC-C where they can initiate and participate in vascular injury associated with AIDS-related cardiomyopathy.

Cervical dysplasia in women infected with the human immunodeficiency virus (HIV): a correlation with HIV viral load and CD4+ count.

OBJECTIVES: The incidence of cervical dysplasia and carcinoma is known to be increased in HIV-infected women. In addition, there is a positive correlation between HIV viral load (VL), CD4+ count, and opportunistic infections, as well as the incidence of various malignancies. This study compares HIV VL and CD4+ count with the presence of cervical dysplasia, as well as with the degree of severity of dysplasia. METHODS: A retrospective chart review of 350 HIV-infected women with polymerase chain reaction (PCR) quantitation of viral load was performed to identify 82 women with biopsy-proven cervical dysplasia and 25 women without any significant cervical pathology. The highest plasma VL within a year of the patients' cervical pathology and corresponding CD4+ count was selected and compared with cervical pathology. Univariate and multivariate statistical analysis using Student's t test and logistic regression analysis was used to analyze the significance of other risk factors such as age, race, smoking history, history of illicit drug use, and prior sexually transmitted disease as well as of viral load and CD4+ count. RESULTS: Of 82 cases of cervical dysplasia, 33 (40.24%) were mild (CIN I), 47 (57.32%) were either moderate or severe (CIN II-III) dysplasia, and 2 demonstrated invasive squamous cell carcinoma (2.44%). A significant statistical difference was found when comparing either HIV plasma VL or CD4+ T-cell counts with the presence of cervical dysplasia on biopsy (P < 0.005). However, only CD4+ count was identified as an independent risk factor for the presence of cervical dysplasia after multivariate analysis. CONCLUSION: In our population, there is a significant correlation between VL and CD4+ count and the presence of cervical dysplasia. However, VL does not appear to be an independent risk factor for cervical dysplasia in this population of HIV-infected women.

Effects of norepinephrine, HIV type 1 infection, and leukocyte interactions with endothelial cells on the expression of matrix metalloproteinases.

The expression of matrix metalloproteinases (MMPs) associated with AIDS-related cardiomypathies and cocaine abuse was examined in an in vitro coculture model. Human peripheral blood mononuclear cells (PBMCs), HIV infected or uninfected, were placed in coculture with primary human cardiac microvascular endothelial cells (HMVEC-C) in the presence or absence of the cocaine-inducible catecholamine norepinephrine (NE). Culture supernatants were assayed for MMP-1, -2, -3, -7, -9, and -13, and for tissue inhibitor of metalloproteinase 1 (TIMP-1) and TIMP-2, by enzyme-linked immunosorbent assay. Low levels of constitutively expressed MMP-1 and -2 were detected in individual cultures of HMVEC-C and PBMCs. NE did not induce MMP or TIMP expression by HMVEC-C and caused modest increases (3- to 4-fold) in MMP-1 and -2 by uninfected PBMCs. Increased levels of NE-induced MMP-1 (5-fold) and MMP -2 (15-fold) were detected in cocultures of HMVEC-C and uninfected PBMCs. HIV infection enhanced MMP-1 (46-fold) and MMP-2 (48-fold) and active MMP-7 (33-fold) and MMP-9 (50-fold) by PBMCs. Coculture of HIV-infected PBMCs with HMVEC-C increased MMP-1 (110-fold) and MMP-2 (307-fold) but not active MMP-7 and -9. The combination of NE, HIV infection, and coculture increased MMP-1 (126-fold) and MMP-2 (467-fold), and active MMP-7 (65-fold) and MMP-9 (75-fold). MMP-3 or-13 was not detected in any of the treatment groups and TIMP-1 and -2 appeared inversely proportional to the observed levels of MMPs. These results suggest that HIV infection, NE, and leukocyte endothelial interactions demonstrate separate and overlapping cooperative effects on the regulation of expression of TIMPs and MMPs associated with AIDS-related cardiomyopathies.

Use of a novel marker, calponin, for myoepithelial cells in fine-needle aspirates of papillary breast lesions.

Benign and malignant papillary lesions of the breast (PBL) can be difficult to distinguish in fine-needle aspirates (FNA). This study evaluates the use of smooth muscle actin (SMA) and a new smooth muscle-specific protein, calponin, for identifying myoepithelial cells (MEC) by immunohistochemical methods in paraffin-embedded cell blocks of FNA of PBL. Formalin-fixed, paraffin-embedded cell blocks of 40 cases of PBL were stained using SMA and calponin, steam heat-induced epitope retrieval, and an avidin biotin-complex technique. Staining was evaluated in MEC, epithelial, and stromal cells. The diagnosis of benign vs. malignant papillary lesion was made by using cytomorphological criteria and the presence/absence of MEC in the cell block. These results were compared to the original cytologic and subsequent histologic diagnoses. Of 40 cases of FNA diagnosed as PBL, there were 27 intraductal papillomas (IP), 6 papillary lesions with atypical features (PLAF), and 7 papillary carcinomas (PC). In all of the IP, MEC stained both with SMA and calponin. None of the PC cases was positive for MEC with calponin, and 2 out of 7 cases were weakly positive by SMA. In 6 cases of PLAF, 2 were negative for MEC, both by SMA and calponin, and a malignant papillary lesion was confirmed by histology. The remaining 4 cases were positive for MEC with both markers and were confirmed to be benign by histology. SMA stained stromal cells strongly in all of the cases where stroma was present (18 of a total of 40 cases of PBL), while calponin stained stroma focally in only 7 cases. More than half of all cases had nuclear staining of epithelial cells with SMA; calponin did not show any nuclear staining.

Effects of UVB radiation on cytokine generation, cell adhesion molecules, and cell activation markers in T-lymphocytes and peripheral blood HPCs.

BACKGROUND: Immunomodulatory effects of UV light have increasingly become a focus in transfusion medicine, BMT and transplantation immunology. In the transplant setting, the use of UVB radiation may reduce or abolish T-cell activation without compromising either bone marrow (BM) engraftment or graft-versus-leukemia effect. In this study, BM and apheresis-derived peripheral blood HPCs were used to investigate the effects of UVB on colony-forming ability, CD34+ cell viability, and growth potential, as well as on the secretion of MNC cytokines and the expression of cell surface markers and adhesion molecules. STUDY DESIGN AND METHODS: After UVB radiation, enriched populations of T cells and antigen-presenting cells (APCs) were treated with PHA, and the MNC response was measured, as was colony-forming ability. CD34+ cells were quantified and their growth potential was determined in culture. Next, T-cell activation status, cell adhesion molecule and cell surface activation marker expression, and cytokine profiles were evaluated, and cytokine mRNA was quantitated. Parallel studies were done in unirradiated control cell populations. RESULTS: Low-dose (10 mJ/cm(2)) UVB mitigates MNC proliferative responses by 94 percent while maintaining 60 and 80 percent of colony-forming ability in peripheral blood HPC and BM preparations, respectively, and >50 percent of colony-forming ability in CD34+ cell-enriched samples. Low-dose UVB radiation also significantly reduces T-cell production of TNFalpha, TNFalpha mRNA, TNFbeta, IL-2, and IL-6 and downregulates T-cell expression of CD28, CD25, CD69, and intercellular adhesion molecule 1. CONCLUSION: These findings have shown that a "window" of low-dose UVB radiation (10 mJ/cm(2)) exists, at which BM- and peripheral blood-derived MNC proliferation is inactivated, while the HPCs are relatively spared. UVB light selectively affects T cells, while APCs are resistant to low doses of UVB. UVB radiation also alters the expression of some cell surface markers and cytokines that are important in T-cell activation pathways. Reduction of T-cell activation without cytocidal effect may allow UVB radiation to become an immunomodulating agent in BM or HPC transplantation.

Utility of fine needle aspiration in HIV-positive patients with corresponding CD4 counts. Four years' experience in a large inner city hospital.

OBJECTIVE: To assess the utility of fine needle aspiration (FNA) in human immunodeficiency virus (HIV)-positive patients with corresponding CD4 count analysis. STUDY DESIGN: The study group consisted of 108 FNA specimens from 80 patients performed from January 1991 to December 1994. RESULTS: FNAs were sub-typed into four categories: lymph nodes (59 specimens), masses (26 specimens), salivary glands (19 specimens) and breast (4 specimens). Thirty-three were diagnosed as reactive lymph nodes, 15% as benign lymphoepithelial lesions and 9% as granulomas; 9% revealed acute inflammation, 5% were positive for malignant lymphoma, and 3% were suspicious for Kaposi's sarcoma. Differences in CD4 counts were statistically significant for specific subsets of HIV-related illnesses. General trends were noted in mean CD4 counts for specific sub-groups of HIV-related illnesses. CONCLUSION: Material adequate for culture can be obtained with the FNA procedure. FNA in skilled hands is a very useful simple and cost-effective procedure for the diagnosis of HIV-related lesions and in the management of these patients. This study suggested that mean CD4 counts are statistically significant in specific subsets of HIV related illnesses.

Congenital malformations of the respiratory tract.

Malformations of the respiratory tract were found in 21 out of 205 foetuses (10%) in whom various congenital malformations had been prenatally detected by ultrasonography and amniocentesis. Pulmonary hypoplasia was the most common of all pulmonary malformations and was established in 17 cases (81%). Lung alobulation was established in two cases (9.5%), and pulmonary cysts were recorded in another two cases in post-mortem examinations. Correlations established between ultrasonographic and pathomorphological findings were not satisfactory as only 29% of all ultrasonographic diagnosis were complete and correct. Hence, much closer cooperation between the pathologist and clinician is essential to all investigations of congenital malformations, in particular to those of complex nature.

Angiomyolipoma in the transplanted kidney. A case report.

Angiomyolipoma is a very rare benign renal tumor. This paper presents the autopsy finding of an angiomyolipoma in the transplanted kidney.

[Civilian massacre near Podravska Slatina, 3 September 1991]. / Pokolj civila blizu Podravske Slatine 3. rujna 1991.

Twenty one civilians, 5 women and 16 men, were found dead in their doorways and yards after Serbian terrorists attacked the village of Cetekovac on 3 September 1991. The age of the decedents ranged from 18 to 91 years. The oldest victims were women (aged 63, 68, 72, 86 and 91). The wounds found on 19 decedents were characteristic of the long-range gunshot wounds, with projectiles fired mostly from the back or/and the side of the body. The autopsy of one decedent (J. B.) revealed that he died from two stabbing wounds and that those were the only wounds inflicted to the body. The body of the decedent (M. S.) was heavily carbonized so that the cause of the death or even whether he was alive when his body was set on fire could not be estimated.

[Comparison of clinical and pathomorphologic diagnosis in autopsies of primary microcellular bronchial carcinoma]. / Usporedba klinickih i patomorfoloskih dijagnoza u obduciranih sa primarnim mikrocelularnim karcinomom bronha.

Correlation between clinical and pathomorphological diagnosis in 117 autopsy cases with primary bronchial oat cell carcinoma has been done. In more than 1/3 of all cases clinicians did not recognise primary bronchial neoplasm, in 1/4 they made the proper diagnosis of oat cell carcinoma, and in rest of the cases clinical diagnosis was "Carcinoma bronchi", without proper histological type, or they only made the doubt about bronchial carcinoma. Such diversity between clinical and pathomorphological diagnosis could be explained by specific biological behaviour, rather nonspecific clinical signs, and most of all, an increasing rate of this carcinoma in younger patients. In conclusion, it is necessary to point out the importance of interdisciplinary approach, in the first place pathologists and clinicians, what might certainly contribute to the quality of work for both.