Heterogeneous Infiltration Research Articles

Histopathological characterization of corrosion product associated adverse local tissue reaction in hip implants: a study of 285 cases.

BackgroundAdverse local tissue reaction (ALTR), characterized by a heterogeneous cellular inflammatory infiltrate and the presence of corrosion products in the periprosthetic soft tissues, has been recognized as a mechanism of failure in total hip replacement (THA). Different histological subtypes may have unique needs for longitudinal clinical follow-up and complication rates after revision arthroplasty. The purpose of this study was to describe the histological patterns observed in the periprosthetic tissue of failed THA in three different implant classes due to ALTR and their association with clinical features of implant failure.MethodsConsecutive patients presenting with ALTR from three major hip implant classes (N = 285 cases) were identified from our prospective Osteolysis Tissue Database and Repository. Clinical characteristics including age, sex, BMI, length of implantation, and serum metal ion levels were recorded. Retrieved synovial tissue morphology was graded using light microscopy. Clinical characteristics and features of synovial tissue analysis were compared between the three implant classes. Histological patterns of ALTR identified from our observations and the literature were used to classify each case. The association between implant class and histological patterns was compared.ResultsOur histological analysis demonstrates that ALTR encompasses three main histological patterns: 1) macrophage predominant, 2) mixed lymphocytic and macrophagic with or without features of associated with hypersensitivity/allergy or response to particle toxicity (eosinophils/mast cells and/or lymphocytic germinal centers), and 3) predominant sarcoid-like granulomas. Implant classification was associated with histological pattern of failure, and the macrophagic predominant pattern was more common in implants with metal-on-metal bearing surfaces (MoM HRA and MoM LHTHA groups). Duration of implantation and composition of periprosthetic cellular infiltrates was significantly different amongst the three implant types examined suggesting that histopathological features of ALTR may explain the variability of clinical implant performance in these cases.ConclusionsALTR encompasses a diverse range of histological patterns, which are reflective of both the implant configuration independent of manufacturer and clinical features such as duration of implantation. The macrophagic predominant pattern and its mechanism of implant failure represent an important subgroup of ALTR which could become more prominent with increased length of implantation.

Modelling the spatial heterogeneity and molecular correlates of lymphocytic infiltration in triple-negative breast cancer.

Lymphocytic infiltration is associated with a favourable prognosis and predicts response to chemotherapy in many cancer types, including the aggressive triple-negative breast cancer (TNBC). However, it is not well understood owing to the high levels of spatial heterogeneity within tumours, which is difficult to analyse by traditional pathological assessment. This paper describes an unbiased methodology to statistically model the spatial distribution of lymphocytes among tumour cells based on automated analysis of haematoxylin-and-eosin-stained whole-tumour section images, which is applied to two independent TNBC cohorts of 181 patients with matched microarray gene expression data. The novelty of the proposed methodology is the fusion of image analysis and statistical modelling for an integrative understanding of intratumour heterogeneity of lymphocytic infiltration. Using this methodology, a quantitative measure of intratumour lymphocyte ratio is developed and found to be significantly associated with disease-specific survival in both TNBC cohorts independent to standard clinical parameters. The proposed image-based measure compares favourably to a number of gene expression signatures of immune infiltration. In addition, heterogeneous immune infiltration at the morphological level is reflected at the molecular scale and correlated with increased expression of CTLA4, the target of ipilimumab. Taken together, these results support the fusion of high-throughput image analysis and statistical modelling to offer reproducible and robust biomarkers for the objective identification of patients with poor prognosis and treatment options.

Short wavelength lateral variability of lithospheric mantle beneath the Middle Atlas (Morocco) as recorded by mantle xenoliths

The Middle Atlas is a region where xenolith-bearing volcanism roughly coincides with the maximum of lithospheric thinning beneath continental Morocco. It is therefore a key area to study the mechanisms of lithospheric thinning and constrain the component of mantle buoyancy that is required to explain the Moroccan topography. Samples from the two main xenolith localities, the Bou Ibalghatene and Tafraoute maars, have been investigated for their mineralogy, microstructures, crystallographic preferred orientation, and whole-rock and mineral compositions. While Bou Ibalghatene belongs to the main Middle Atlas volcanic field, in the ‘tabular’ Middle Atlas, Tafraoute is situated about 45km away, on the North Middle Atlas Fault that separates the ‘folded’ Middle Atlas, to the South-East, from the ‘tabular’ Middle Atlas, to the North-West. Both xenolith suites record infiltration of sub-lithospheric melts that are akin to the Middle Atlas volcanism but were differentiated to variable degrees as a result of interactions with lithospheric mantle. However, while the Bou Ibalghatene mantle was densely traversed by high melt fractions, mostly focused in melt conduits, the Tafraoute suite records heterogeneous infiltration of smaller melt fractions that migrated diffusively, by intergranular porous flow. As a consequence the lithospheric mantle beneath Bou Ibalghaten was strongly modified by melt–rock interactions in the Cenozoic whereas the Tafraoute mantle preserves the record of extensional lithospheric thinning, most likely related to Mesozoic rifting. The two xenolith suites illustrate distinct mechanisms of lithospheric thinning: extensional thinning in Tafraoute, where hydrous incongruent melting triggered by decompression probably played a key role in favouring strain localisation, vs. thermal erosion in Bou Ibalghatene, favoured and guided by a dense network of melt conduits. Our results lend support to the suggestion that lithospheric thinning beneath the Atlas mountains results from the combination of different mechanisms and occurred in a piecewise fashion at a short wavelength scale.

An animal model of type A cystinuria due to spontaneous mutation in 129S2/SvPasCrl mice.

Cystinuria is an autosomal recessive disease caused by the mutation of either SLC3A1 gene encoding for rBAT (type A cystinuria) or SLC7A9 gene encoding for b0,+AT (type B cystinuria). Here, we evidenced in a commonly used congenic 129S2/SvPasCrl mouse substrain a dramatically high frequency of kidney stones that were similar to those of patients with cystinuria. Most of 129S2/SvPasCrl exhibited pathognomonic cystine crystals in urine and an aminoaciduria profile similar to that of patients with cystinuria. In addition, we observed a heterogeneous inflammatory infiltrate and cystine tubular casts in the kidney of cystinuric mice. As compared to another classical mouse strain, C57BL/6J mice, 129S2/SvPasCrl mice had an increased mortality associated with bilateral obstructive hydronephrosis. In 129S2/SvPasCrl mice, the heavy subunit rBAT of the tetrameric transporter of dibasic amino acids was absent in proximal tubules and we identified a single pathogenic mutation in a highly conserved region of the Slc3a1 gene. This novel mouse model mimicking human disease would allow us further pathophysiological studies and may be useful to analyse the crystal/tissue interactions in cystinuria.

IL-17 producing NK cells are suspected to be critical for the IL-17 dependent TLR-3 triggered aggravation of experimental asthma

Exacerbations are a typical characteristic of asthma that causes considerable morbidity on patients. The inflammatory phenotype of acute asthma exacerbations has been reported to be characterized by a heterogeneous infiltrate with eosinophils and large numbers of neutrophils in sputum as well as broncho-alveolar lavage (BAL). Epidemiological surveys identified viral infection of the respiratory tract as the main trigger. Double stranded RNA is produced as an intermediate during replication of all major respiratory viruses and can be sensed by toll-like receptor 3 (TLR3), which could therefore play a critical role in the pathogenesis of acute asthma exacerbation. Our study aimed at i) establishing a mouse model of TLR3 trigged asthma exacerbation, ii) clarifying the underlying mechanisms, and iii) identifying the cell type(s) directing the inflammatory response.

Small Molecule PRIMA-1 met Sensitizes Waldenstrom Macroglobulinemia Cells To Apoptosis and Displays Synergistic Cytotoxicity With Bortezomib

BackgroundWaldenstrom macroglobulinemia (WM) is a lymphoplasmacytic lymphoma characterized by heterogeneous infiltration of bone marrow and IgM monoclonal gammopathy. WM constitutes 1-2% of haematological malignancies and patients exhibit diverse outcome. Given the current therapies WM remains incurable with high rate of relapse, therefore, the quest for finding a more effective drug continues. PRIMA-1met is a small molecule with the ability to restore wild type conformation to mutant P53 and to activate wild type P53. PRIMA-1met has shown significant anti-tumour activity both in vitro and in vivo by inducing apoptosis in several human cancers including haematological malignancies and is currently under phase I/II clinical trials. To date, the effects of PRIMA-1met have not been explored in WM. Here we examined the antitumor activity of PRIMA-1met alone and in combination with dexamethasone or bortezomib in WM. DesignWM cell lines, BCWM-1(Wild type P53) and MWCL-1 (mutant P53), were used for these studies. Cellular proliferation, viability, migration and percentage of cells undergoing apoptosis in WM cells treated with PRIMA-1met or DMSO control were evaluated using trypan blue, MTT assay, Boyden chamber assay and Annexin-V staining methods respectively. The status of key role players in apoptosis and cell cycle regulators were examined following treatment with PRIMA-1metusing qRT-PCR and Western blot analyses. Cell viability was also investigated by combining PRIMA-1metwith either dexamethasone or bortezomib in WM cells by MTT assay. ResultBoth BCWM-1 and MWCL-1 cells showed significant decrease in cell viability after exposure to escalating doses of PRIMA-1met with observed IC50 of 30 μM in BCWM-1 cells and 28 μM in MWCL-1 cells after 48 hours. Two primary WM patients' samples exposed to increasing concentration of PRIMA-1metdemonstrated significant decrease in cell viability with IC50of 30 and 10 μM after 48 hours. Importantly, peripheral and bone marrow mononuclear cells of 3 healthy donors were subjected to PRIMA-1metand no significant cytotoxicity was observed. Both cell lines showed an increase in apoptosis after PRIMA-1mettreatment in a dose-dependent manner compared to control DMSO treatment. In BCWM-1, cell proliferation, measured by counting viable cells after 7 days, was significantly inhibited by PRIMA-1metcompared to DMSO control (∼54% fewer cells when treated with 25 μM PRIMA-1met, p<0.05). Decrease in cell migration by as much as 28% at 25 μM compared to DMSO control (p<0.001) was also observed after 8 hours of treatment with PRIMA-1met. Expressions of P53 and its downstream target p21 were elevated in PRIMA-1mettreated cells compared to DMSO control. In addition, qRT-PCR studies of 50 genes associated with apoptosis also demonstrated enhanced expression of pro-apoptotic markers such as PUMA, Noxa, caspase 8 and 9, BIM and BAD, which were further confirmed for their protein expressions by Western blot analysis. Finally, PRIMA-1met(25 μM) was found to exert synergistic cytotoxic effect in combination with dexamethasone (2 μM) in MWCL-1 cells (Combination index (CI)=0.5). PRIMA-1met(25 μM) also displayed synergism with bortezomib (3 μM) in its cytotoxicity toward BCWM-1 cells (CI=0.8). ConclusionsOur results demonstrate that PRIMA-1met induces apoptosis irrespective of P53 status in WM cells. It also provides the preclinical framework for evaluation of PRIMA-1met either alone or in combination with bortezomib or dexamethasone as a novel therapeutic approach for the treatment of WM patients. Disclosures:Chen:Roche: Honoraria; Johnson & Johnson: Consultancy, Research Funding; Lundbeck: Consultancy; Celgene: Consultancy, Research Funding; GlaxoSmithKline: Research Funding.

Correlation Between Sonography and Antibody Activity in Patients With Hashimoto Thyroiditis

Patients with Hashimoto thyroiditis show structural changes of the thyroid that can be identified by a variety of sonographic criteria. We conducted this study to investigate whether there is a correlation between sonography and antibody activity and to assess the role of sonography in the diagnosis and follow-up of Hashimoto thyroiditis. In addition, we present a new classification system (termed the VESINC system [volume, echogenicity, sonographic texture, pseudonodular hypoechoic infiltration, nodules, and cysts]), which helps improve the clarity of sonographic findings. The study included 223 consecutive patients with previously diagnosed Hashimoto autoimmune thyroiditis who attended the thyroid clinic of the German Armed Forces Central Hospital in Koblenz for follow-up examinations between 2006 and 2008. Laboratory tests were performed to measure the levels of free triiodothyronine, free thyroxine, thyrotropin, anti-thyroglobulin antibodies (TgAbs), and antithyroid peroxidase antibodies (TPOAbs). Sonography was performed according to a strict protocol. We then assessed whether a correlation existed between antibody activity and the 6 sonographic variables of the VESINC system. Hypoechogenicity, heterogeneity, and pseudonodular hypoechoic infiltration were associated with significantly higher TPOAb activity (P < .001). There were no significant correlations between the other sonographic variables examined (cysts, nodules, and volume) or the biometric data with the TPOAb and TgAb levels. In addition, an assessment of TgAb levels did not show significant differences in correlations with any of the sonographic variables. Sonography is a noninvasive diagnostic imaging modality that provides information about the level of inflammatory activity. Markedly decreased echogenicity, heterogeneity, and multifocal pseudoinodular hypoechoic infiltration are indicative of a high level of inflammatory activity. The sonographic classification system presented here (VESINC system) can be a useful tool for comparing sonographic findings in a rapid and objective manner during follow-up of Hashimoto thyroiditis.

Changes in Water Flow and Solute Transport Pathways During Long‐Term Column Experiments

Column experiments are often used to study transport properties of sediments to predict the fate of contaminants in the subsurface. However, water flow in column experiments is rarely monitored over the entire length of experiments, despite the known impact of biogeochemical processes on pore structures. To study if flow path changes occur over time, water flow and solute transport were investigated in a homogeneous, nearly saturated column by conducting three tracer experiments over 7 mo. Water flow and transport parameters were determined from tracer breakthrough curves using different model approaches. The initial homogeneous transport was adequately described by a simple advection‐dispersion model. However, after some months, the porous medium changed from being uniform to non‐uniform. The observed bimodal breakthrough curves were simulated with a simple multi‐flow advection‐dispersion and a dual‐permeability model. Both models supported the development of non‐uniform water flow and solute transport due to flow paths changes. Those changes were attributed to clogging of small pores near the column inlet due to microbial growth and calcite precipitation leading to a heterogeneous infiltration front. The results highlight the need to determine transport properties continuously over the course of column experiments to reliably predict parameters for groundwater flow and understand contaminant transport into aquifers.

Abstract 1612: Targeting intercellular adhesion molecule-1 (ICAM-1) prolongs glioblastoma survival in combination with bevacizumab .

Abstract Glioblastoma is the most common malignant brain tumor and is characterized by cellular heterogeneity, vascular proliferation and extensive tissue infiltration. Analysis of gene expression data from orthotopic glioma stem cells with acquired resistance to bevacizumab therapy identified over expression of intercellular adhesion molecule 1 (ICAM1, CD54) in resistant tumors. ICAM1 is a cell adhesion glycoprotein of the immunoglobulin supergene family which interacts with β2 integrins, mediates leukocyte transendothelial migration and T cell activation during inflammatory processes. ICAM1 over expression in tumors resistant to antiangiogenic therapy was validated by real time PCR and Western blot. In a panel of glioma stem cell lines, ICAM1 expression was higher in mesenchymal compared to proneural cell lines. GFP-tagged ICAM1 shRNA lentivirus was used to knockdown ICAM1 in multiple cell lines. We injected shICAM1 NSC11 and scramble glioma stem cells into the brain of nude mice. Mice bearing tumors formed from shICAM1 NSC11 cells survived significantly longer than mice injected with scramble control cells. Tumor size was significantly decreased in mice bearing tumors formed from shICAM1 cells than that in mice bearing tumors from GFP-tagged NSC11 control cells. Knocking-down ICAM1 suppresses tumor invasion both in vitro and in vivo. We next examined the mechanism of ICAM1 over expression after treated with anti-VEGF therapy. We observed that ICAM1 over expression correlated with hypoxia-inducible factor by immnofluorescence analysis in tumor tissue. Furthermore, we found that ICAM1 protein expression was markedly increased after NSC11 and NSC17 cells under hypoxic condition in a time-dependent manner. Furthermore, hypoxia-induced p-STAT3 increased transcription of ICAM1, which was inhibited by an inhibitor of the JAK/STAT3 pathway. Our studies identify ICAM1 as a potentially important mediator of tumor migration/invasion in glioblastoma. Targeting ICAM1 may provide a new strategy to prolong the efficacy of antiangiogenic therapy and prevent the invasive phenotype. Citation Format: Yuji Piao, Ji Liang, Verlene Henry, Lindsay Holmes, John F. de Groot. Targeting intercellular adhesion molecule-1 (ICAM-1) prolongs glioblastoma survival in combination with bevacizumab . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1612. doi:10.1158/1538-7445.AM2013-1612

Genomic Abnormalities of Waldenström Macroglobulinemia and Related Low-Grade B-Cell Lymphomas

Waldenström macroglobulinemia (WM) is a lymphoproliferative disease characterized by a heterogeneous lymphoplasmacytic bone marrow infiltrate and monoclonal immunoglobulin M production. WM shows similarities in presentations with related B-cell malignancies, sometimes making it difficult to distinguish them. To better characterize the genetic basis of WM, we performed a comparative genomic analysis with the related entities, lymphoplasmacytic lymphomas without monoclonal immunoglobulin M protein, marginal zone lymphomas, chronic lymphocytic leukemia, and monoclonal gammopathy of undetermined significance. Overall, WM shows a very stable karyotype and shares most of the chromosomal abnormalities with most of the indolent B-cell malignancies. Trisomy 4 is unique to WM; however, no candidate genes have been identified in the chromosome. Abnormalities that affect myeloid differentiation primary response 88 (MYD88)--interleukin-1 receptor-associated kinase 4 (IRAK4) and nuclear factor kappa B (NF-κB) signaling pathways were found in a significant proportion of WM cases, which suggest their relevance in the pathogenesis of the disease and opening new avenues that may be a guide to design novel therapeutic approaches.

Recruitment of a Myeloid Cell Subset (CD11b/Gr1mid) via CCL2/CCR2 Promotes the Development of Colorectal Cancer Liver Metastasis

Liver metastasis from colorectal cancer is a leading cause of cancer mortality. Myeloid cells play pivotal roles in the metastatic process, but their prometastatic functions in liver metastasis remain incompletely understood. To investigate their role, we simulated liver metastasis in C57BL/6 mice through intrasplenic inoculation of MC38 colon carcinoma cells. Among the heterogeneous myeloid infiltrate, we identified a distinct population of CD11b/Gr1(mid) cells different from other myeloid populations previously associated with liver metastasis. These cells increased in number dramatically during establishment of liver metastases and were recruited from bone marrow by tumor-derived CCL2. Liver metastasis of Lewis lung carcinoma cells followed this pattern but this mechanism is not universal as liver colonization by B16F1 melanoma cells did not recruit similar subsets. Inhibition of CCL2 signaling and absence of its cognate receptor CCR2 reduced CD11b/Gr1(mid) recruitment and decreased tumor burden. Depletion of the CD11b/Gr1(mid) subset in a transgenic CD11b-diphtheria toxin receptor mouse model markedly reduced tumor cell proliferation. There was no evidence for involvement of an adaptive immune response in the prometastatic effects of CD11b/Gr1(mid) cells. Additionally, an analogous myeloid subset was found in liver metastases of some colorectal cancer patients. Collectively, our findings highlight the importance of myeloid cells--in this case a selective CD11b/Gr1(mid) subset--in sustaining development of colorectal cancer liver metastasis and identify a potential target for antimetastatic therapy.

Molecular pathogenesis of Waldenstrom's macroglobulinemia.

Waldenström's macroglobulinemia is an indolent, lymphoproliferative disease, characterized by a heterogeneous lymphoplasmacytic bone marrow infiltrate and high immunoglobulin M production. While technological advances over the past several decades have dramatically improved the possibilities of studying the molecular basis of Waldenström's macroglobulinemia, the pathogenesis of the disease remains fragmented. Undoubtedly, research has been successful in uncovering underlying aberrations and deregulated mechanisms in this disease, providing useful information for identifying biomarkers for disease diagnosis, risk stratification and therapeutic intervention, but there is still a long way to go before the pathogenesis of Waldenström's macroglobulinemia is fully revealed. In addition, the low number of in vitro or in vivo models significantly challenges extensive analysis. In this manuscript, we review the molecular basis of this disease.

Abstract 1388: Acquired resistance to anti-VEGF therapy in glioblastoma is associated with an inflammatory and mesenchymal phenotype

Abstract Glioblastoma is the most common malignant brain tumor and is characterized by rapid angiogenesis-dependent (re)growth, cell heterogeneity, and extensive local tissue infiltration. Antiangiogenic therapy, among the most promising treatment developments, rapidly reduces vascular permeability and delays glioblastoma progression but the therapy itself ultimately promotes an aggressive treatment-resistant phenotype. The aim of the present study was to identify mechanisms responsible for glioblastoma resistance to antiangiogenic therapy. When mice bearing U87 and NSC11 xenografts treated with bevacizumab became moribund, tumor tissue was extracted to obtain tumor cells with acquired resistance to bevacizumab. U87 and NSC11 cells were dissociated and cultured in serum-containing and stem cell media, respectively. To verify resistance, the resistant cells were expanded in vitro and then re-implanted orthotopically in nude mice. Mice were randomized to receive bevacizumab or vehicle and followed for survival. As anticipated, tumors formed by parental U87 and NSC11 cells were sensitive, whereas tumors obtained at the time of acquired resistance to anti-VEGF therapy were resistant to bevacizumab and did not have prolongation of survival compared to untreated controls. To elucidate the molecular mechanisms underlying resistance to antiangiogenic treatment, we performed gene expression profiling using Affymetrix U133Plus_2.0 arrays comparing untreated and bevacizumab-treated tumors. Comparison of anti-VEGF therapy-resistant cell lines to untreated controls demonstrated an increase in genes associated with a mesenchymal phenotype. Antiangiogenic therapy increased the expression of genes of mesenchymal origin, cellular migration/invasion, and inflammation including chemokine secretion, myeloid cell chemotaxis and multiple markers reflecting a pro-inflammatory environment. Consistent with these data, mice bearing U87 resistant tumors showed significantly greater infiltration of F4/80+ myeloid cells compared to wild-type tumors. Comparing the mesenchymal gene signature from Phillips et al with the gene changes in our experiments using Gene Set Enrichment Analysis (GSEA v2.07, Broad Institute, MIT), we show that NSC11 tumors treated with bevacizumab showed a highly significant correlation to the published mesenchymal gene signature. In addition to the pro-inflammatory changes, invasion-related genes were also upregulated. We found the U87 and NSC11 resistant cells have significantly higher invasion rates in vitro compared with U87 and NSC11 parental cell lines. Our studies identify prominent mechanisms of glioblastoma resistance to antiangiogenic therapy. A better understanding of resistance may provide new strategies to prolong the efficacy of this therapy and accelerate the integration of combination therapies into clinical trials. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1388. doi:1538-7445.AM2012-1388

Discovered on gastrointestinal stromal tumour 1 (DOG1): a useful immunohistochemical marker for diagnosing chondroblastoma

Cellular areas of chondroblastoma are composed of polygonal chondroblasts with indented nuclei and scattered osteoclast-type multinucleated cells. To learn more about the phenotype of chondroblasts, we investigated the expression of several established immunohistochemical markers in chondroblastomas. Nine chondroblastomas were analysed using immunohistochemical antibodies [CD34, α-smooth muscle actin (α-SMA), DOG1, CD117, AE1/AE3 and CD163]. Ten chondromyxoid fibromas, seven giant cell tumours of bone and four foetal proximal femurs were also analysed. The cellular areas of each chondroblastoma contained nests of DOG1(+) αSMA(+) CD117(-) CD34(-) chondroblasts, a phenotype that was not detected in chondromyxoid fibroma cases or in giant cell tumours. Although AE1/AE3 was expressed in all chondroblastomas, the staining intensity and proportion of the positive cells varied widely. Intra-lesional CD163(+) macrophages were detected in all cases of chondroblastoma, chondromyxoid fibroma and giant cell tumours. Our results demonstrated nests of membranous DOG1(+) chondroblasts located within cellular portions of chondroblastoma containing diffuse heterogeneous infiltrates of mostly DOG1(-) chondroblasts, CD163(+) macrophages and multinucleated osteoclastic giant cells. Thus, chondroblastoma can be added to the tumours that are usually positive for DOG1, alongside gastrointestinal stromal tumour (GIST), rare solid-pseudopapillary neoplasms of the pancreas and exceptional mesenchymal tumours including uterine type retroperitoneal leiomyoma, peritoneal leiomyomatosis and synovial sarcoma.

Effects of Land Cover and Fertilization Method on Water Flow and Solute Transport in Five Lysimeters: A Long‐Term Study Using Stable Water Isotopes

Land cover and agricultural management practices can significantly influence soil structure. However, little is known about how fertilizer applications and land cover affect soil hydrology and groundwater recharge over long time periods. The objective of this study was to use stable water isotopes as environmental tracers to provide additional information required for better understanding of water flow and solute transport processes in the unsaturated zone influenced by land cover and type of fertilizer applications. Five lysimeters containing undisturbed soil monoliths from the same agricultural field site were investigated over a period of 5 yr. Liquid cattle slurry and solid animal manure were applied to the maize (Zea mays L.) and winter rye (Secale cereale L.) lysimeters. The grass–clover lysimeter was treated with mineral fertilizer. Quantitative influence of land cover and type of fertilizer application on water flow and solute transport was evaluated for all lysimeters using a modified version of HYDRUS‐1D. The highest drainage was observed in the maize lysimeter treated with cattle slurry, and the lowest in the grass lysimeter treated with mineral fertilizer. Pronounced differences in water contents and estimated saturated hydraulic conductivities between the lysimeters were restricted to the upper 25 to 30 cm of the soil. In particular, the lysimeters treated with animal manure had higher porosities, indicating a higher content of organic matter. Main differences in discharge between the lysimeters were observed in spring and during the plant growth periods, indicating the importance of nonuniform, patchy infiltration patterns during snow melt and of root water uptake, respectively. Mean water flow velocities, transit times, and effective water contents were estimated from the stable water isotope data, providing evidence on the impact of land cover and type of fertilizer application. We found smaller mean transit times in the maize lysimeters and for soils with liquid cattle slurry applications. Simulations indicate that numerical modeling can reproduce the general trend of water flow and isotope transport. Despite differences in mean transit times, fitted dispersivities were all in the same range, suggesting similar soil structures in the five lysimeters. However, more data for calibration and more information about heterogeneous infiltration would be required to improve the model accuracy. In general, stable water isotopes clearly contributed an added value, elucidating differences in mean flow parameters between the lysimeters. Thus, they provided evidence of the impacts of land cover and fertilizer applications, which are not obvious from water balance and mean discharge rates alone.

Implications of Self-Potential Distribution for Groundwater Flow System in a Nonvolcanic Mountain Slope

Self-potential (SP) measurements were conducted at Mt. Tsukuba, Japan, which is a nonvolcanic mountain, to infer groundwater flow system in the mountain. Survey routes were set around the northern slope, and the reliability of observed SP anomaly was checked by using SP values along parallel survey routes; the error was almost within 10 mV. The FFT analysis of the spatial SP distribution allows us a separation of raw data into two components with shorter and longer wavelength. In the shorter (altitudinal) wavelength than ∼200 meters, several positive SP peaks of more than 100 mV in magnitude are present, which indicate shallow perched water discharges along the slope. In the regional SP pattern of longer wavelength, there are two major perturbations from the general trend reflecting the topographic effect. By comparing the SP and hydrological data, the perturbation around the foothill is interpreted to be caused by heterogeneous infiltration at the ground surface. The perturbation around the summit is also interpreted to be caused by heterogeneous infiltration process, based on a simplified numerical modeling of SP. As a result, the SP pattern is well explained by groundwater flow and infiltration processes. Thus, SP data is thought to be very useful for understanding of groundwater flow system on a mountain scale.

Autoimmune Thyroid Diseases

Autoimmune thyroid disease is characterized by the presence of autoantibodies against thyroid peroxidase (TPO), thyroglobulin (Tg), and the thyroid simulating hormone recep­ tor (TSHR). The thyroid gland is a site of autoantibody secretion in autoimmune thyroid disease by the B cells infiltrated into the thyroid. Hashimoto’s thyroiditis, a chronic autoim ­ mune thyroid disease, characterized by the occurrence of high levels of serum thyroid an­ tibodies for TPO and Tg and goiter, is the most common type of thyroiditis. A firm, diffuse, painless goiter is the most common initial finding in Hashimoto’s thyroiditis. Some patients have atrophic thyroid glands rather than goiter, which may represent the final stage of thyroid failure in Hashimoto’s thyroiditis. Levothyroxine is the treatment of choice for Ha­ shimoto’s thyroiditis presenting overt hypothyroidism. Patients with Hashimoto’s thyroid­ itis and a thyroid nodule should undergo fine ­needle aspiration biopsy to rule out lym­ phoma and thyroid carcinoma. Graves’ disease is the most common cause of spontaneous hyperthyroidism in patients younger than 40 years of age. Patients with Graves’ disease re­ veal heterogeneous lymphocytic infiltration without follicular destruction and also show various clinical presentations.

Modeling Field-Scale Bioretention Cells with Heterogeneous Infiltration Media

To address increasing stormwater management concerns in metropolitan and suburban areas, bioretention systems are a mitigation technology that helps address both water quantity and quality. However, it is critical for stormwater managers and engineers to model the hydraulic performance of these systems before investing in the infrastructure. This means an appropriate model must be selected to efficiently reflect important aspects of the given site and design. This work investigated the ability of a one-dimensional model to simulate water movement through a heterogeneous bioretention cell. For model validation, two full-size bioretention cells in Grove, Oklahoma, were flooded a total of three times, and parameters related to overflow, drainage and relative change in soil moisture were measured. Observed values were compared to predictions using an uncalibrated model previously developed and run with area-weighted soil parameters (“original model”). In addition, observations were compared to an uncalibrated “revised model,” which allowed modeling of distinct infiltration media. The revised model allowed for two separate soil types in the horizontal plane and simulated maximum subsurface drainage flow rate (23.6% to 33.7% from observed), volume (7.9% to 38.9% from observed), and timing (14.7% to 92.5% from observed) better than the original model, but the original model generally simulated overflow volume (12.2% to 77.1% from observed) and peak overflow rate (3.6% to 9.6% from observed) more closely. It was concluded that the revised model was more appropriate for modeling heterogeneous systems when concerns exist about timing of hydrographs and all underdrain parameters.

Parametric Histogram Analysis of Dynamic Contrast-enhanced MRI in Multiple Myeloma: A Technique to Evaluate Angiogenic Response to Therapy?

From dynamic contrast-enhanced magnetic resonance imaging, it is known that microcirculation patterns in multiple myeloma differ depending on the infiltration pattern. The purpose of this study was to evaluate histogram analysis of dynamic contrast-enhanced magnetic resonance imaging in MM to monitor early treatment response on the basis of microcirculation patterns. A total of 51 patients with multiple myeloma requiring therapy were examined. Dynamic contrast-enhanced magnetic resonance imaging of the lumbar spine was performed before and after conventional or high-dose chemotherapy with autologous stem cell transplantation. Statistical analysis included 245 vertebrae and dynamic microcirculation parameters as displayed in histograms. Resulting parameters (amplitude, exchange rate constant, skewness, kurtosis, and left shift) were correlated with therapeutic response. More than 70% of histograms derived from the microcirculation parameters showed a difference between the maximum peak before and after therapy (left shift). However, there was no significant difference between the particular treatment. Significantly different skewness of amplitude in 98% and kurtosis of exchange rate constant (94.1% and 98%) were seen in the patients who responded to treatment (P for each < .05). Histogram analysis revealed early changes after therapy resulting in a shift toward more (kurtosis) and lower values (skewness) of microcirculation parameters. Therefore, histogram analysis can determine and describe if a chosen therapy works at all. However, there were no differences between the chosen therapies. This needs to be reevaluated in a larger number of treated patients. Histogram analysis can also be an adjunct to a subjective visual analysis but is hampered by heterogeneous infiltration pattern seen in multiple myeloma.

Reduced intensity conditioning allogeneic hematopoietic stem cell transplant could be beneficial to angioimmunoblastic T-cell lymphoma patients with hemophagocytic lymphohistiocytosis

Dear Editor, T-cell non-Hodgkin’s lymphomas (NHLs) are a group of heterogeneous diseases with more aggressive behavior and dismal outcome than B-cell NHLs and account for less than 10% of the cases of aggressive NHLs in Western countries [1]. The outcome of T-cell NHL is even worse when it occurs in combination with hemophagocytic lymphohistiocytosis (HLH); this combination presents with fever, cytopenia, liver dysfunction, hepatosplenomegaly, hypertriglyceridemia, and hyperferritinemia [2, 3]. We report the case of a patient who had angioimmunoblastic T-cell lymphoma (AITL) and HLH and was successfully treated by allogeneic hematopoietic stem cell transplant (HSCT) with a reduced-intensity conditioning (RIC) regimen. The patient was a 62-year-old woman who did not have any other systemic diseases and presented with fever of up to 38.5°C of 1-week duration; she lost 20 kg in 6 months as well. Physical examination showed neck lymph node enlargement and hepatosplenomegaly. Abdominal computed tomography showed hepatosplenomegaly and retroperitoneal lymphadenopathy. Cervical lymph node biopsy was performed and the biopsy specimen showed heterogeneous infiltration of medium-sized atypical lymphocytes, with proliferation of post-capillary venules (Fig. 1a) and features of hemophagocytosis (Fig. 1b); it was immunohistochemically positive for CD3 and CD4, but negative for CD8, CD30, CD56, and CD20. AITL was diagnosed on the basis of these biopsy results. In situ hybridization detected Epstein–Barr virus-encoded RNA. Bone marrow examination showed prominent hemophagocytosis, but without evidence of lymphoma involvement. The patient had normal prothrombin time, activated partial thromboplastin time, fibrinogen levels, and liver and renal functions. However, the presence of anemia (hemoglobin 8.4 gdl, reference range 12–14), hyperferritinemia (ferritin 26,400 μg l, reference range 10– 120), elevated lactate dehydrogenase (673 Ul, reference range 120–240), hypertriglyceridemia (triglyceride 278 mg dl, reference range <200), and profound hemophagocytosis in both lymph nodes and bone marrow confirmed that she had HLH. We initiated treatment with one cycle of cyclophosphamide, adriamycin, vincristine, and prednisolone (CHOP), but the fever recurred in 2 weeks. Salvage chemotherapy with one cycle of etoposide, methylprednisolone, cytarabine, and cisplatin (ESHAP) and two cycles of mesna, ifosfamide, mitoxantrone, and etoposide (MINE) was administered. Her cervical lesions partially responded to these treatments; however, positron emission tomography and computed tomography detected a new nodular lesion in the patient’s J.-T. Yu :W.-L. Hwang : C.-L. Teng (*) Division of Hematology/Oncology, Department of Medicine, Taichung Veterans General Hospital, 160, Section 3, Chungkang Road, Taichung 407, Taiwan e-mail: drteng@vghtc.gov.tw