Complete metabolic response (CMR) in positron emission tomography–computed tomography (PET‐CT) scans may have prognostic significance in patients with marginal zone lymphomas (MZL)

Although clinical use of positron emission tomography–computed tomography (PET‐CT) scans is well established in aggressive lymphomas, its prognostic value in marginal zone lymphoma (MZL) remains yet unclear. Hence, we investigated potential role of PET‐CT in predicting MZL patients' outcomes following systemic chemotherapy. A total of 32 patients with MZL who received first‐line chemotherapy were included in the analysis. They all underwent pretreatment, interim, and posttreatment PET‐CT scans. The primary objective was to evaluate the role of complete metabolic response (CMR) in posttreatment PET‐CT scans in predicting progression‐free survival (PFS). Compared with non‐CMR group, 5‐year PFS rate was significantly higher in patients who achieved CMR in posttreatment PET‐CT (54.2% vs 0.0%, P = .003) and also in patients gaining CMR in interim PET‐CT scans (62.5% vs 15.6%, P = .026). Interestingly, early CMR group, who achieved and maintained CMR in both interim and posttreatment PET‐CT scans, showed significantly higher 5‐year PFS than those with delayed or never CMR group (62.5% vs 37.5% vs 0%, P = .008). Therefore, interim and/or posttreatment CMR can be prognostic at least in these subsets of patients with MZL treated with chemotherapy.     

Intravascular papillary endothelial hyperplasia of the neck masquerading as malignancy on fine-needle aspiration cytology

Papillary endothelial hyperplasia (PEH) is an exuberant, usually intravascular endothelial proliferation that, in many respects, mimics angiosarcoma. A case of PEH originally suggestive of embryonal carcinoma by fine-needle aspiration is presented. A 12-year-old boy presented with a palpable mass on the right side of the neck. The mass was subsequently aspirated. Cytopathologic features showed cohesive sheets of polygonal pleomorphic cells with vesicular nuclei and prominent multiple nucleoli in a hemorrhagic background. Cytologic findings were strongly suggestive of metastatic embryonal carcinoma. There was no evidence of a primary lesion. After the mass was surgically excised, the pathologic findings showed PEH. A retrospective immunocytochemical stain for factor VIII-related antigen on a destained ethanol-fixed smear confirmed the endothelial nature of the polygonal cells. A vascular lesion should be considered, especially when atypical polygonal cells in a hemorrhagic background are present, as they were in this case.     

Gender-specific molecular heterosis of dopamine D2 receptor gene (DRD2) for smoking in schizophrenia

We examined the genetic effect of DRD2 A1 allele in 167 Korean schizophrenics in relation to their smoking habit. Although there was no apparent difference in the genotype distributions of DRD2 gene among the female schizophrenics (n = 66), the male counterpart (n = 101) showed significant differences in their genotype distributions. The comparison between male smoking and non-smoking patients showed the difference in genotype distribution (P = 0.010) with a higher prevalence of A1 allele (P = 0.020) and frequency of heterozygotes (P = 0.005), but not frequency of the A1 allele. The A1A2 heterozygotes male showed significantly higher smoking rate compared to the A1A1 or A2A2 homozygotes male, and non-smokers were deficient in heterozygotes. By contrast, among female schizophrenics, the heterozygotes showed a lower smoking rate than homozygotes and there were more heterozygotes in non-smokers. The deviation from Hardy-Weinberg expectations was observed in male and female non-smokers showing quite opposite profiles. Highly significant differences were seen between male and female non-smokers in A1 prevalence (P = 0.001), genotype distribution (P = 0.00011), and frequency of heterozygotes (P = 0.00003), but not in A1 frequency. The analyses from both male and female as one group showing no significant difference in the genotype distributions between smokers and non-smokers could be explained by the gender difference in the genetic effect of DRD2 A1 allele. Our findings present the gender-specific molecular heterosis of DRD2 gene in relation specifically to the smoking status of schizophrenic patients. They indicate the importance of heterosis and gender effects that should be taken into consideration for the association studies.     

Comparison of polymerase chain reaction with histopathologic features for diagnosis of tuberculosis in formalin-fixed,paraffin-embedded histologic specimens

Objective.-To investigate the relationship between various histopathologic features and the results of the tuberculosis (TB)-polymerase chain reaction (PCR) method in routinely submitted histologic specimens for the histopathologic diagnosis of TB. Design.-We used 95 formalin-fixed, paraffin-embedded tissue blocks from 81 patients who were clinically suspected of having TB. We assessed the presence of histopathologic features including well-formed granuloma, poorly formed granuloma, caseous necrosis, and Langhans-type giant cells. We performed nested PCR for IS6110 and Ziehl-Neelsen staining for acid-fast bacilli (AFB). Results.-Of the 81 patients studied, 53 patients had chronic granulomatous inflammation, whereas 28 patients had only chronic inflammation without definite granulomatous inflammation. Of the 53 cases with chronic granulomatous inflammation, 17 (32%) were AFB positive and 36 (68%) were TB-PCR positive. Among cases with chronic granulomatous inflammation, the percentage that were positive and negative by TB-PCR differed significantly with the presence of various histopathologic features. All of the 13 cases with well-formed granuloma, caseous necrosis, and Langhans-type giant cells were TB-PCR positive; however, 10 (36%) of the 28 cases with chronic inflammation without granulomatous lesions were also TB-PCR positive. Conclusions.-TB-PCR is a rapid, sensitive method for the diagnosis of TB in routinely processed formalin-fixed, paraffin-embedded histologic specimens and is readily available in histopathology laboratories. We recommend use of TB-PCR when TB is suspected clinically, especially in cases of chronic inflammation without definite evidence of granulomatous inflammation.     

Expression and localization of the transforming growth factor-beta type I receptor and Smads in preneoplastic lesions during chemical hepatocarcinogenesis in rats

Little is known about the involvement of Smad-related molecules in the regulation of the Transforming Growth Factor (TGF)-beta signaling pathway during hepatocarcinogenesis, particularly with respect to preneoplastic lesions of a rat liver. The aims of this study were to investigate the localizations and temporal expressions of TGF-beta Receptor Type 1 (TGR1) and Smads during the promotion stage of chemical hepatocarcinogenesis in rats. We investigated expressions and localizations of TGR1, Smad2, Smad4, and Smad7 by using semi-quantitative RT-PCR and immunohistochemistry in preneoplastic lesions during rat chemical hepatocarcinogenesis induced by Solt and Farber's method. The down-regulation of TGR1, Smad2, and Smad4 was evident during the later steps of the promotion stage of chemical hepatocarcinogenesis. In contrast with other Smads, increased Smad7 expression was evident during the later steps of the promotion stage. Also immunohistochemistry revealed that the main site of TGR1, Smad2, Smad4, and Smad7 expression was mainly in hepatocytes of the preneoplastic lesions of a rat liver. Dysregulation of the downstream effectors of TGF-beta such as TGR1, Smad2, Smad4 and, Smad7 might contribute to the progression of preneoplastic lesions during chemical hepatocarcinogenesis in a rat.     

Studies on the mechanisms of active ion fluxes across alveolar epithelial cell monolayers

Summary To investigate the cell physiologic and biological properties of the alveolar epithelium, we studied rat alveolar epithelial cell monolayers grown on permeable supports in primary culture. Type II alveolar epithelial cells were disaggregated using elastase, and partially purified on a discontinuous metrizamide gradient. These isolated cells were plated onto tissue culture-treated Nuclepore membrane filters at 1.5×10⁶ cells/cm² and maintained in a humidified incubator (5% CO₂ in air, 37° C). After 2 days in culture, the bathing media on both sides of the cell monolayers were changed to fresh culture medium, thus removing nonadherent cells (mostly leukocytes). These monolayers exhibit a high transmonolayer resistance (>2000 -cm²) and actively transport ions. Radionuclide flux studies indicate that Na⁺ is the predominant ionic species absorbed actively under baseline conditions, accounting for about 80% of the total active ion transport. Cl^– seems to be passively transported across the epithelium. However, when the epithelium is exposed to a beta-agonist (terbutaline), active absorption of Na⁺ is increased and active absorption of Cl^– occurs. Although it is clear that both active Na⁺ and Cl^– transport are dependent on Na⁺/K⁺-ATPase activity, and that Na⁺ enters cells predominantly through channels, the specific mechanisms by which Cl^– enters and exits the alveolar epithelial cells remain unclear. The stimulated reabsorption of Na⁺ and Cl^– may be important in helping to remove excess fluid from alveolar air spaces in the lung.     

Trp-Lys-Tyr-Met-Val-D-Met is a chemoattractant for human phagocytic cells

Trp-Lys-Tyr-Met-Val-D-Met (WKYMVm) is a synthetic peptide that stimulates phosphoinositide (PI) hydrolysis in human leukocytes. The peptide binds to a unique cell surface receptor(s). Recently we had demonstrated that human neutrophils, monocytes, and B lymphocytes express this peptide-specific receptor and that stimulation of human leukocytes with the peptide leads to activation of the oxidative respiratory system and the bactericidal activity of neutrophils or monocytes. In this study we showed that the peptide induces chemotaxis of phagocytic leukocytes and studied the signaling pathway leading to chemotaxis in human monocytes. The peptide-induced monocyte chemotaxis is pertussis toxin (PTX)-sensitive. This fact correlates with the peptide's stimulation of PI hydrolysis and intracellular Ca2+ ([Ca2+]i) release, which is also PTX-sensitive. We demonstrate that the peptide-specific receptor is different from receptor(s) for monocyte chemoattractant protein-1 (MCP-1). We also show that intracellular signaling of WKYMVm leading to monocyte chemotaxis is different from that of MCP-1. The peptide-mediated monocyte chemotaxis is insensitive to protein kinase C (PKC) inhibitor (GF109203X) and butan-1-ol, ruling out PKC and phospholipase D participation in this process. On the other hand, a tyrosine kinase inhibitor (genistein) and RhoA inhibitor (C3 transferase) curtailed the peptide-induced chemotaxis in a concentration-dependent manner, implying the involvement of tyrosine kinase and RhoA, respectively. Treatment of human monocytes with the peptide stimulates tyrosine phosphorylation of several cellular proteins, including p125FAK and Pyk2 and translocation of RhoA from the cytosol to the membrane. We conclude that WKYMVm induces chemotaxis of human phagocytic leukocytes via unique receptors and signaling.     

Acute promyelocytic leukemia is a distinct subset of acute myelocytic leukemia with unique clinicopathologic characteristics including longer duration of relapse free survival: experience in 13 cases.

Acute promyelocytic leukemia(APL) is a subtype of acute myelocytic leukemia(AML) associated with unique features such as the presence of atypical promyelocytes and bleeding tendency due to disseminated intravascular coagulation(DIC). In a retrospective study, we analyzed 96 cases of AML seen at our hospital between June, 1989 and December 1993. Thirteen cases of APL(14%) were identified and their clinicopathologic characteristics were analyzed. The 86 cases of other types of AML served as controls. The distinct clinicopathologic features of APL as contrasted to other types of AML included younger age of patients, shorter duration of symptom before diagnosis, higher level of albumin at presentation, and a higher proportion of patients having coagulation abnormalities (75 vs. 25%). Bone marrow cellularity was higher in APL when compared to other types of AML (100 vs. 90%, P = 0.013). Of 13 patients with APL, 4 died of bleeding/sepsis between days 2 to 4 after admission. Seven of 9 patients who received induction therapy achieved complete remission(CR). CR rate in APL was similar to other types of AML (78 vs. 64%, P = 0.743). Five of seven patients who achieved CR remain in continuous CR at 9+ to 42+ months. CR duration is significantly longer in APL when compared to other types of AML (P = 0.029). In conclusion, this study showed that APL is a distinct entity among subtypes of AML with clinically significant bleeding tendency and rapidly fatal course if untreated. With appropriate antileukemic therapy, CR can be achieved in the majority of patients and the patients show a longer duration of CR when compared to other types of AML.     

Significance of 99mTc-ECD SPECT in acute and subacute ischemic stroke: comparison with MR images including diffusion and perfusion weighted images

99mTc-ECD SPECT is valuable for the evaluation of cell viability and function. The purpose of the present study was to evaluate the significance of 99mTc-ECD brain SPECT in ischemic stroke. We compared 99mTc-ECD brain SPECT with perfusion and diffusion weighted images (PWI, DWI). Ten patients with acute and early subacute ischemic stroke were included in this prospective study. T2-weighted images (T2WI), DWI, PWI and 99mTc-ECD SPECT were obtained during both the acute/early subacute and late subacute stages. In the case of PWI, time to peak (TTP) and regional cerebral blood volume (rCBV) maps were obtained. The rCBV map and 99mTc-ECD SPECT images were compared in 8 lesions using DeltaAI. The asymmetry index (AI) was calculated as (Ci - Cc) X 200 / (Ci + Cc); where Ci is the mean number of pixel counts of an ipsilateral lesion and Cc is the mean number of pixel counts of the normal contralateral hemisphere. DeltaAI was defined as AIacute - AIsubacute in the ischemic core and periphery. PWI and 99mTc-ECD SPECT detected new lesions of the hyperacute stage or of evolving stroke more accurately than T2WI and DWI. 99mTc-ECD SPECT was able to localize the infarct core and peri-infarct ischemia in all lesions in both the acute and the subacute stages. DeltaAI was higher in the rCBV map than in the 99mTc-ECD SPECT images in the ischemic core (p = 0.063) and in the periphery (p = 0.091). In the 99mTc-ECD SPECT images, DeltaAI was higher in the ischemic core than in the periphery (p = 0.028). During the subacute stage, 99mTc-ECD SPECT detected all the lesions without the pseudonormalization seen in the MR images of 5/11 lesions. Based on this study, 99mTc-ECD SPECT is comparable to PWI in terms of its ability to detect acute stroke and is more useful than PWI in the case of subacute infarction.     

Fluorescent magnetic nanohybrids as multimodal imaging agents for human epithelial cancer detection.

Cetuximab conjugated fluorescent magnetic nanohybrids (CET-FMNHs) were synthesized for detection of human epithelial cancer via magnetic resonance (MR) and optical imaging. Spherical FMNHs consist of MnFe(2)O(4) magnetic nanocrystals encapsulated in pyrene-labeled PCL-b-PMAA as a surfactant prepared by a nano-emulsion method. FMNHs demonstrated excellent colloidal stability and biocompatibility for biomedical application. Antibody conjugated fluorescent magnetic nanohybrids (CET-FMNHs) served as effective agents for both magnetic resonance (MR) and fluorescence optical imaging of cancer cell lines.