Features Of Advanced Disease Research Articles

Discoidin Domain Receptor-1 Deficiency Attenuates Atherosclerotic Calcification and Smooth Muscle Cell-Mediated Mineralization

Intimal calcification is a feature of advanced atherosclerotic disease that predicts a two- to eightfold increase in the risk of coronary events. Type I collagen promotes vascular smooth muscle cell-mediated calcification, although the mechanism by which this occurs is unknown. The discoidin domain receptor 1 (DDR1) is a collagen receptor that is emerging as a critical mediator of atherosclerosis. To determine whether DDR1 is involved in intimal calcification, we fed male Ddr1(-/-);Ldlr(-/-) and Ddr1(+/+);Ldlr(-/-) mice an atherogenic diet for 6, 12, or 24 weeks. DDR1 deficiency significantly reduced the calcium content of the aortic arch, and microcomputed tomography demonstrated a significant decrease in hydroxyapatite deposition after 24 weeks of atherogenic diet. Reduced calcification was correlated with decreases in macrophage accumulation and tumor necrosis factor alpha staining, suggesting that the reduction in calcification was in part due to decreased inflammation. The chondrogenic markers type II collagen, type X collagen, and Sox-9 were expressed within the mineralized foci. An in vitro assay performed with vascular smooth muscle cells revealed that DDR1 was required for cell-mediated calcification of the matrix, and Ddr1(+/+) smooth muscle cells expressed more alkaline phosphatase activity, whereas Ddr1(-/-) smooth muscle cells expressed elevated levels of mRNA for nucleotide pyrophosphatase phosphodiesterase 1, an inhibitor of tissue mineralization. Taken together, our results demonstrate that DDR1 mediates an important mechanism for atherosclerotic calcification.

Increased levels of Vascular Cell Adhesion Molecule-1 (VCAM-1) and Inter-Cellular Adhesion Molecule-1 (ICAM-1) Correlate with Advanced Disease Features and Poor Survival in Newly Diagnosed Patients with Multiple Myeloma. Reduction Post-Bortezomib- and Lenalidomide-Based Regimens.

Abstract 1824Poster Board I-850Interactions between myeloma (MM) cells and bone marrow stromal cells (BMSCs) are strongly implicated in the biology of MM. The aim of this study was to evaluate the serum levels of adhesion molecules, such as VCAM-1 (CD106), ICAM-1 (CD54), P-, L- and E-selectin in patients with MM and explore possible correlations with clinical and laboratory data. The study population included 87 newly diagnosed patients (42M/45F; median age 68 years): 59 with symptomatic MM, 21 with asymptomatic MM (AMM) and 7 with MGUS, as well as 21 MM patients at first relapse (11M/10F, median age 69 years) who received the combination of bortezomib/dexamethasone (VD) and 20 MM patients at first relapse (11M/9F, median age 68.5 years) who were treated with the combination of lenalidomide plus low-dose dexamethasone (Rd). The aforementioned adhesion molecules were measured in the serum of newly-diagnosed patients before the administration of any kind of therapy, in relapsed patients on Day 1 of cycle 1 and on the last day of cycle 4 and in 43 healthy controls using ELISA method (R&D Systems, Minneapolis, MN, USA). Patients with newly-diagnosed or relapsed MM had increased levels of all studied molecules compared to controls (p<0.01), while in MGUS only serum VCAM-1 and ICAM-1 levels were elevated compared to controls (p<0.01). Newly-diagnosed patients with symptomatic MM had increased levels of VCAM-1 (mean±SD: 1168.5±810.4 ng/ml) and ICAM-1 (371.0±162.7 ng/mL) when compared to AMM patients (642.6±340.9 ng/ml, p<0.0001; and 274.4±65.5 ng/ml, p=0.002, for VCAM-1 and ICAM-1, respectively) and to MGUS patients (629.8±228.5 ng/ml, p=0.012; and 247.9±53.9, p=0.009, for VCAM-1 and ICAM-1, respectively). Furthermore, newly-diagnosed symptomatic MM had increased levels of E-selectin (43.2±20.0 ng/ml) compared to AMM (33.6±16.6 ng/ml, p=0.047). VCAM-1 was lower in patients with ISS-1 (768.2±225.1 ng/ml) compared to patients with ISS-2 (1121.7±991.2 ng/ml) and ISS-3 (1456.8±785.7 ng/ml; ANOVA p=0.04), while P-selectin was higher in ISS-1 (172.7±76.6 ng/ml) compared to ISS-2 (118.7±75.5 ng/ml) and ISS-3 MM (108.3±76.4; ANOVA p=0.042). For all newly-diagnosed patients, there was a strong correlation between VCAM-1 and ICAM-1 (r=0.598, p<0.0001). Serum VCAM-1 showed strong positive correlations with β2-microglobulin (r=0.564, p<0.0001), urea (r=0.384, p=0.001) and creatinine (r=0.376, p=0.001) and negative correlation with Hb (r=-0.346, p=0.002). Similarly, ICAM-1 positively correlated with β2-microglobulin (r=0.340, p=0.003), creatinine (r=0.290, p=0.01) and urea (r=0.254, p=0.025), and negatively correlated with Hb (r=-0.237, p=0.037). Serum P-selectin positively correlated with platelet counts (r=0.555, p<0.0001), Hb (r=0.416, p<0.0001) and albumin (r=0.270, p=0.017), but negatively correlated with β2-microglobulin (r=-0.383; p=0.001) and creatinine (r=-0.294, p=0.009). For L-selectin there was a positive correlation with albumin (r=0.370; p=0.001). The median follow-up of patients with newly-diagnosed symptomatic MM was 22 months (range: 4-54 months) and the median OS was 42 months. Increased levels of VCAM-1, ICAM-1 and L-selectin predicted for inferior survival. In particular, patients with VCAM-1 >1358.5 ng/ml had a median OS of 20 months in comparison to 42 months of all others (p=0.006), while patients with elevated ICAM-1 (>400.6 ng/ml) had a median OS of 13 months compared to 42 months of all others (p<0.0001) and patients with L-selectin >928.2 ng/ml had a median OS of 23 months compared to 42 months of all others (p=0.024). MM patients at first relapse had increased levels of VCAM-1 and ICAM-1 even compared to newly-diagnosed symptomatic MM patients (p<0.01). Both BD and Rd administration reduced dramatically serum VCAM-1 and ICAM-1 after 4 cycles of therapy (p<0.01 for all comparisons) but had no effect on the levels of selectins. The reduction of VCAM-1 and ICAM-1 was more pronounced in responders than in non-responders (p=0.032). In conclusion, patients with newly diagnosed MM have increased serum levels of VCAM-1 and ICAM-1 that correlate with advanced disease features and poor survival suggesting an important role in the biology of the disease. Selectins seem also to participate in MM pathogenesis. The administration of novel agents such as bortezomib and lenalidomide resulted in the reduction of VCAM-1 and ICAM-1 and supports a direct effect on the adhesion of MM cells to BMSCs. DisclosuresNo relevant conflicts of interest to declare.

High Serum Lactate Dehydrogenase (LDH) Is An Important Prognostic Factor in the Era of Novel Agents and Adds to the Prognostic Value of the International Staging System (ISS) in Patients with Multiple Myeloma.

Abstract 1819Poster Board I-845Several older studies have shown that high serum LDH is associated with features of advanced disease and with an inferior survival of symptomatic patients with MM who require treatment. It is however unclear whether LDH may add to the prognostic value of ISS and whether it may retain its prognostic significance in patients who have been exposed to novel agent-based therapies either at diagnosis or later in the course of their disease. In order to address these issues we analyzed 996 consecutive symptomatic patients who were included in the data base of the Greek Myeloma Study Group and who received frontline treatment between January 1995 and December 2008. Elevated serum LDH to ≥300 IU/L (normal levels <225 IU/L) was observed in 11% of patients. High LDH was seen more often in patients with impaired performance status (p<0.01), with anemia (p<0.01), with thrombocytopenia (p<0.01), with renal impairment (p<0.01), with high ISS (p<0.01), and with hypercalcemia (p=0.01). The median survival of all patients was 40 months with a clear improvement for patients who started treatment after January 2000 as compared to patients who started treatment before that date (50 months versus 31 months; p<0.01). Multiple clilnical and laboratory variables correlated with the probability of survival in univariate analysis. A multivariate analysis showed that the following variables had an independent prognostic significance: LDH (p<0.001), ISS (p<0.001), performance status (p<0.001), age (p<0.001) and platelet count (p<0.001). The median survival of patients with high versus normal LDH was 15 months versus 44 months (p<0.001). High LDH was observed in 7% of patients with ISS-1, in 10% of ISS-2 and 12% of ISS-3. Within each ISS subgroup the presence of high LDH was associated with a worse median survival. In ISS-1 the median survival of patients with high LDH was 22 months (CI 95%: 10-35) while the median survival of those with normal LDH was 76 months (CI 95%: 61-91; p<0.01). Similarly in ISS-2 the median survival of patients with high and normal LDH was 11 months (CI 95%: 7-14) and 40 months (CI 95%: 32-48), respectively (p<0.001), while in ISS-3 it was 17 months (CI 95%: 11-23) and 27 months (CI 95%: 21-33), respectively (p<0.01). Subsequently, patients were separated into two groups: patients who started treatment between January 1995 and December 1999 and patients who started therapy after January 2000 i.e. patients who had access to novel agent-based therapy. In both groups the presence of high LDH was related with statistically worse survival. In patients who received treatment before January 2000, the median survival in the high LDH group was 10 months (CI 95%: 4-16) versus 36 months in the normal LDH group (CI 95%: 31-42; p<0.001). Similarly, in patients who received treatment after January 2000, the median survival in the high LDH group was 21 months (CI 95%: 12-29) versus 51 months in the normal LDH group (CI 95%: 40-63; p<0.001). We conclude that serum LDH is a readily available and inexpensive variable which has a major impact on the survival of patients with myeloma even when they belong to a low or intermediate ISS subgroup and even when they receive novel agent-based therapy. DisclosuresNo relevant conflicts of interest to declare.

Diffuse MRI Marrow Pattern Correlates with Increased Angiogenesis, Advanced Disease Features and Poor Prognosis in Newly-Diagnosed Patients with Multiple Myeloma Treated with Novel Agents.

Abstract 829The aim of this study was to evaluate the prognostic value of bone marrow magnetic resonance imaging (MRI) in newly-diagnosed myeloma (MM) patients who received novel agent-based therapy and to explore possible correlations of MRI pattern with clinical and laboratory data. Eighty-two consecutive MM patients (43M/39F, median age: 65 years) at diagnosis were studied. MRI of the spine was performed within 1-2 weeks following diagnosis. T1-weighted, STIR and contrast-enhanced T1-weighted sagittal MR images of the thoracic and lumbar spine were obtained with a 1.5 T unit (Phillips, Eindhoven, the Netherlands). Marrow involvement was characterized as normal, focal, diffuse or variegated. Microvessel density (MVD) was evaluated in marrow trephine biopsies at the time of diagnosis. The following serum indices of bone metabolism and angiogenesis were measured on the day of MRI: i) osteoclast stimulators [sRANKL, osteoprotegerin (OPG), osteopontin (OPN) and macrophage inflammatory protein-1alpha (MIP-1alpha)], ii) dickkopf-1 (Dkk-1), iii) bone resorption markers [C- and N-terminal cross-linking telopeptide of collagen type-I (CTX and NTX, respectively) and TRACP-5b], iv) bone formation markers [bone alkaline phosphatase (bALP) and osteocalcin (OC)], and v) angiogenic cytokines [VEGF, VEGF-A, angiogenin (ANG), angiopoietin-1 (ANGP-1), angiopoietin-2 (ANGP-2) and bFGF]. MRI evaluation of the spine revealed that 34 (41.5%) patients had focal, 26 (31.7%) diffuse, 18 (22%) normal, and 4 (4.9%) had a variegated pattern of marrow involvement. Low-grade angiogenesis, as assessed by MVD, was present in 32 (39%) patients, while 33 (40%) had intermediate-grade and 17 (20%) patients had high-grade angiogenesis. Twenty-one of 26 (80%) patients with a diffuse MR pattern had intermediate or high-grade angiogenesis in contrast to 14/34 (41%) patients with focal involvement (p=0.01) and 12/18 (66%) with normal MR pattern (p=0.037). Patients had increased values of VEGF (p<0.001), VEGF-A (p<0.001), ANGP-2 (p<0.001) and bFGF (p=0.001), and reduced values of ANGP1/ANGP2 ratio (p<0.01) compared to healthy controls (n=36). Patients with a diffuse pattern were the only patients who had increased ANG compared to controls (p=0.004). Patients with diffuse pattern had higher levels of serum VEGF and VEGF-A compared to patients with normal (p=0.028 and p=0.006, respectively) and focal pattern (p=0.009 and p<0.01, respectively) and borderline elevated ANG compared to normal pattern (p=0.06). Myeloma patients had increased values of sRANKL (p<0.001), sRANKL/OPG ratio (p=0.004), NTX (p<0.001), CTX (p<0.001), TRACP-5b (p<0.001), Dkk-1 (p=0.01), and OPN (p<0.001) and borderline reduced values of bALP (p=0.09) compared to controls. Patients with normal MRI pattern showed no difference in terms of Dkk-1 and bone formation markers compared to controls. Patients with diffuse pattern of marrow involvement had reduced values of bone formation markers (p=0.01), while patients with focal pattern had only a borderline reduction of OC (p=0.09). Both diffuse and focal MRI patterns had increased Dkk-1 levels. All abnormal MRI patterns had increased levels of NTX, CTX and TRACP-5b and increased levels of osteoclast stimulators sRANKL/OPG, MIP-1alpha and OPN. Diffuse and variegated patterns of infiltration correlated with greater bone marrow plasma cell infiltration (p=0.043) and advanced ISS stage (p=0.018). All patients received a combination regimen that contained at least one novel anti-myeloma agent (IMiD and/or bortezomib) at some point during the course of their disease. The median follow-up of the patients was 25 months. Patients with diffuse or variegated pattern had a median survival of 29 months, patients with focal pattern had a median survival of 62 months, while the median survival of patients with normal MRI pattern has not been reached at the time of the analysis (p=0.009). Multivariate analysis showed that only MRI pattern and ISS stage were independent prognostic factors for survival. In conclusion, our analysis provides strong evidence that diffuse MRI pattern of marrow involvement correlates with increased angiogenesis, adverse disease features and inferior survival in MM patients who were treated with novel agents. Such patients may be considered for upfront treatment with combinations of novel agents. Our results highlight the important prognostic value of MRI in MM and support its routine use in MM patients. Disclosures:No relevant conflicts of interest to declare.

219 How to manage the patient who presents with stage IV colorectal cancer. The role of the colorectal surgeon

Wilms' tumor, or nephroblastoma, is the most common malignant renal tumor of childhood. It occurs with an annual incidence of 7 cases per million children aged less than 15 years.9 Approximately 450 new cases are diagnosed each year in North America. Although at the beginning of this century, most children with Wilms' tumor died of the disease, survival now exceeds 80%.26 This tremendous success story in childhood cancer was facilitated initially by individuals. Subsequent advances were achieved by institutions and cooperative groups. In the past 3 decades, the National Wilms' Tumor Study Group (NWTSG) and the International Society of Paediatric Oncology (SIOP) have contributed to improving the clinical management of children affected by Wilms' tumor. The NWTSG has studied most patients with Wilms' tumor in North America in randomized trials since 1969 and has collected data on more than 6000 patients. Based on a strategy of immediate nephrectomy, the NWTSG recommends early surgical resection of the tumor and affected kidney.35 Subsequently, depending on the histology of the tumor and the clinicopathologic stage, patients should receive chemotherapy. Patients with advanced disease or specific adverse prognostic features should receive additional radiotherapy. In contrast, the SIOP approach recommends preoperative chemotherapy for all tumors, with postoperative treatment for localized tumors dictated according to the stage assigned at the time of surgery.33Although it is a rare disease, Wilms' tumor is one of the childhood cancers that have provided significant information regarding the genetic events leading to the development of cancer in general. Wilms' tumors do not display as much genetic instability69 as adult cancers; hence, the majority of genetic alterations observed are likely to have a role in their development. The systematic study of Wilms' tumor occurring in association with congenital abnormalities has increased understanding of the pathogenesis of this childhood cancer. For example, WT1, the first Wilms' tumor suppressor gene at chromosome 11p13, was identified as a direct result of the study of children with Wilms' tumor who also had aniridia, mental retardation, and genitourinary anomalies. Karyotypic analysis of these children revealed a deletion within the short arm of one copy of chromosome 11.87 Study of the deleted region at band p13 led to the cloning of WT1 in 1990.11, 17, 32 This gene encodes a transcription factor critical to normal kidney and gonadal development.59 Similarly, the study of patients with Wilms' tumor and Beckwith-Wiedemann syndrome, another congenital Wilms' tumor predisposition syndrome, implicated the existence of a second Wilms' tumor suppressor gene, designated WT2. The existence of additional genetic loci involved in the development of Wilms' tumor is suggested by linkage analyses in large pedigrees with familial transmission of susceptibility to Wilms' tumor.70, 84 Loci at 16q,20, 38, 69 1p,38 7p,72, 88, 98 and 17p5, 64 have also been evoked in the biology of Wilms' tumor, although these loci do not predispose to Wilms' tumor but are associated with phenotype or outcome.This article reviews the most important known genetic loci involved in the biology of Wilms' tumor.

Primary tumour diameter as a risk factor for advanced disease features of differentiated thyroid carcinoma

To study the relationship between primary tumour size and the risk of advanced disease features (multifocal or locally invasive disease, lymph-node or distant metastases) in differentiated thyroid carcinoma (DTC). A retrospective chart review study. The study sample comprised 935 papillary (PTC) and 291 follicular thyroid carcinoma (FTC) patients treated in our hospital from 1978 to 2007. Kaplan-Meier analyses and log-rank tests were performed to calculate tumour size-adjusted cumulative risk of advanced disease features. Accounting for primary tumour diameter, there were no significant differences in cumulative risks of multifocal carcinoma (P = 0.12) or distant metastases (P = 0.49) between PTC and FTC. PTC showed higher cumulative risks of local invasion (P < 0.0001) or lymph-node metastases (P < 0.0001). The cumulative risk of tumour multifocality increased 5%/cm of primary tumour diameter. The cumulative risk of local invasion or lymph-node metastases in PTC and of distant metastases in DTC increased exponentially at a threshold tumour diameter of 10 mm. In FTC, lymph-node metastases are associated almost exclusively with primary tumours showing extrathyroidal growth. Starting with a 1 cm primary tumour diameter, increasing tumour size is associated with an exponentially increasing risk of local invasion or lymph-node or distant metastases of DTC. The current classification of carcinomas < 2 cm as T1 is therefore questionable.

Tricuspid and pulmonary valve involvement in carcinoid heart disease

A 55-year-old woman with a history of proven carcinoid syndrome due to an enterochromaffin ileal tumour was evaluated with transthoracic echocardiography for dyspnoea on exertion. The patient had flushing and severe diarrhoea. Urinary excretion of 5-hydroxyindoleacetic acid was 250 mmol/L per 24 hours. Treatment with a somatostatin analogue had been initiated 5 months earlier. Physical examination revealed a 3/6 systolic ejection murmur at the left upper sternal border. No signs of right-sided heart failure were found. The electrocardiographic data were within normal limits. Transthoracic two-dimensional echocardiography revealed restricted motion of the septal and anterior tricuspid valve leaflets both during systole and diastole, leading to an eccentric jet and mild to moderate tricuspid regurgitation (Fig. 1 and Movie 1). Continuous wave (CW) Doppler documented an associated tricuspid stenosis with a mean diastolic gradient of 5 mmHg (Fig. 2). The pulmonary valve was also involved, defined by a limited excursion of the pulmonary valve leaflets without a complete coaptation. CW Doppler of the pulmonary valve demonstrated the presence of both pulmonary stenosis defined by a mean gradient of 40mmHg (Fig. 3) and pulmonary regurgitation (Movie 2). No patent foramen ovale was found at contrast echocardiography. Pulmonary and tricuspid valves were replaced with bioprosthetic valves. A surgical view of the tricuspid and pulmonary valve revealed immobile, thickened and retracted pulmonary and tricuspid valves leaflets (Figs. 4 and 5). Characteristic echocardiographic features of advanced carcinoid heart disease include thickening, retraction of immobile tricuspid valve leaflets with associated tricuspid regurgitation in 90% of cases and pulmonary involvement, mainly immobility of the pulmonary valve cusps, in at least 50% of cases [1]. Contrast transthoracic echocardiography should be performed systematically, searching for a right-to-left atrial shunt through a patent foramen ovate [2].

Features of Duodenal Cancer in Patients With Familial Adenomatous Polyposis

Most patients with familial adenomatous polyposis (FAP) develop duodenal adenomas; duodenal cancer is a major cause of mortality in this patient group. We reviewed cases of duodenal cancer in patients with FAP to identify factors that determine long-term cancer risk. Twenty FAP patients (12 male) were identified from a registry database search. Data from registry and medical notes and endoscopic and histopathologic reports were evaluated. Of the cancers that developed in these patients, 11 were ampullary and 9 were duodenal. The median age at cancer diagnosis was 53 years. Seventeen patients died (median age at death, 57 y; median survival from diagnosis, 11 mo); the cause of death was metastatic or duodenal/ampullary cancer in 14 patients. Fifteen patients presented symptomatically (including 3 interval cancers while on surveillance). Two were diagnosed at surveillance and 3 were diagnosed during surgery performed for endoscopic features of advanced benign disease. Duodenal cancers were associated with a significantly lower mean colonic polyp count than ampullary cancers (496 +/- 282 vs 1322 +/- 735; P = .025); there appeared to be familial clustering of this cancer. When endoscopic data were available (n = 11 of 20), all ampullary cancers arose from ampullas greater than 1 cm. The Spigelman stage did not predict risk of ampullary cancer but did predict duodenal cancer (median stage 2 vs stage 4 for duodenal cancer). Once cancer arises in patients with FAP, prognosis is poor, so cancer prevention should be the main goal. Surveillance intervals should reflect both Spigelman staging and ampullary disease.

Tissue Microarray Analysis of 560 Patients with Colorectal Adenocarcinoma: High Expression of HuR Predicts Poor Survival

The purpose of this study is to characterize the expression of HuR in colorectal carcinoma and determine its correlation with clinical outcome. Differential expression of HuR has been suggested to be of prognostic significance in carcinomas of the ovaries, stomach, and breast. HuR regulates the expression of a variety of proteins critical to carcinogenesis via the pathways of cell-cycle progress, invasion, and metastasis. Increasing evidence suggests that angiogenic pathways are involved. A tissue microarray consisting of tumors from 560 patients with colorectal adenocarcinoma was analyzed for HuR protein expression using a quantitative, automated immunofluorescent microscopy system (AQUA). Clinical data corresponding to each examined specimen collected through an institutional review board (IRB)-approved protocol were analyzed using chi-squared test, Cox regression, and Kaplan-Meier analysis. Median follow-up was 54 months. Along with tumor stage and overall tumor-node-metastasis (TNM) stage, HuR expression was found to be an independent predictor of survival. In patients in the highest quartile of total HuR expression, survival was 22.8 months less than those in the lower quartiles (40.6 versus 63.4 months, p = 0.04). Furthermore, HuR levels correlate positively with expression of vascular endothelial growth factor (VEGF) and CD31, a marker for vascular endothelium. We conclude that expression of high levels of HuR correlates with features of advanced disease and portends poorer survival in patients with colorectal adenocarcinoma. These results further suggest that HuR exerts its tumorigenic effects through VEGF-mediated angiogenesis and may be a novel therapeutic target in colorectal cancer.

High T-Cell Lymphoma Breakpoint 1 (TCL1) Levels Are Associated with Lack of Response and Inferior Outcome Following Fludarabine, Cyclophosphamide, Rituximab (FCR) Frontline Therapy in Patients with Chronic Lymphocytic Leukemia (CLL).

Body: Expression of the human oncogene TCL1 in transgenic mice produces B-cell tumors that resemble human CLL suggesting a role in B-cell tumorigenesis. TCL1 protein levels in CLL vary, with the highest expression seen in the pre-germinal center subtype which is also correlated with expression of ZAP70. We compare here TCL1 and ZAP70 as markers of response and progression following FCR front-line chemotherapy in a large cohort of patients (pts.).Methods: Paraffin-embedded pre-treatment bone marrow specimens from 243 CLL pts. who received FCR as frontline therapy between 11/99 and 01/04 were evaluated for TCL1 expression by immunohistochemistry (IHC) using a mouse monoclonal antibody developed in our laboratory. A three-tier grading system (0–2) for expression levels was used. Data on ZAP70 expression (by IHC) and IgVH mutation status was available for 195 and 76 pts., respectively. The series was evaluated for the endpoints of complete response (CR) rates, CR duration, time to failure (TTF),and overall survival (OS) as previously defined (Tam et al., Blood 2008).Results: 54 (22%) CLL cases expressed no or minimal TCL1 protein (graded as 0), while 143 (59%) cases showed dim/partial TCL1 expression (graded as 1), and 46 (19%) cases expressed moderate to strong TCL1 levels (graded as 2; Table 1). Heterogeneous intratumoral TCL1 expression was seen in a subset of cases, especially within proliferation centers. High TCL1 expression correlated with presenting features of advanced disease, including higher pre-treatment WBC counts (p=0.01), elevated serum beta-2 microglobulin (p=0.01) and unmutated IgVH genes (p = .0007).Most significantly, high TCL1 expression levels predicted failure to attain a CR (p=0.038), shorter TTF (p=0.0003), and inferior OS (p=0.003) following FCR therapy. Although ZAP70 and TCL1 were positively correlated (R = 0.24), TCL(−) cases were found in both the ZAP70(+) and ZAP70(−) subsets. Expression of ZAP70 was also associated with shorter TTF (p=0.004), and OS (p=0.02) but not failure to attain a CR (p=0.93) after FCR therapy.Conclusions: In CLL pts initially treated with FCR, strong TCL1 expression by IHC, unlike ZAP70, is predictor of failure to attain a CR and is a prognostic marker of inferior outcome.TCL1 (n=243) versus ZAP70 (n=195) expression by IHCIHC ZAP(−) (n=75)IHC ZAP(+) (n=120)TCL10 (n=54)23211 (n=143)47692 (n=46)530 [Display omitted]

Pleural Effusion In Patients With Advanced Breast Cancer

Malignant pleural effusion is one of the late manifestations of breast cancer. Of 141 patients admitted for breast cancer in the University of Benin Teaching Hospital, Benin-City, Nigeria, over a six year period (January 2000 – December, 2005), 10(7%) were admitted for the management of moderate to massive pleural effusion. They were all females aged between 32 and 66 (mean 50 years) and had clinical features of advanced disease. Management consisted of relief of dyspnoea by thoracentesis and oxygen administration, analygesics and chemotherapy with the CAF regimen (cyclophosphamide, adriamycin and 5 fluorouracil). They all died within one year of presentation. Malignant pleural effusion from breast cancer signifies advanced disease and carries a poor prognosis. Keywords: Pleural effusion, Breast cancer, Benin-CitySahel Medical Journal Vol. 10 (4) 2007: pp. 137-141

Cost of applying the K/DOQI guidelines for bone metabolism and disease to a cohort of chronic hemodialysis patients

Hyperphosphatemia is a common feature of advanced chronic kidney disease (CKD) and is treated routinely with oral calcium-based phosphate binders. In 2003, the National Kidney Foundation Kidney Disease Outcomes and Quality Initiative (K/DOQI) published Clinical Practice Guidelines (CPGs) for the treatment of Bone Metabolism and Disease in CKD. These advocate broad usage of expensive non-calcium-based phosphate binders such as sevelamer. This study was designed to determine the cost of implementation of the K/DOQI CPGs as they pertain to phosphate binding in a large Canadian hemodialysis (HD) unit. Laboratory and medication data for all chronic HD patients at the Ottawa Hospital were reviewed (n=416). Patients meeting each of the relevant K/DOQI guidelines were identified. Where guidelines would recommend a switch to non-calcium binders, equivalent sevelamer doses were estimated. The cost of implementing each guideline was then calculated individually and an estimate total cost of implementing all the guidelines was derived. Overall, 53% (222) patients fulfilled at least one criterion for sevelamer use. The yearly cost of implementation of the K/DOQI guidelines at this center was estimated at 500,605 dollars (American dollars). Given the significant cost, widespread adoption of the K/DOQI CPGs for Bone Metabolism and Disease should await the publication of compelling data demonstrating significant improved outcomes in patients treated with sevelamer.

HIV-associated dementia

The World Health Organization estimates that worldwide there are 40.3 million people infected with HIV (www.who.int/hiv/epi-update2005_en.pdf). Of these, only 2 million live in developed countries and have access to the cocktail of antiretroviral drugs referred to as highly active antiretroviral therapy (HAART). HIV-associated dementia (HAD) along with its less severe forms of minor and asymptomatic neurocognitive impairment is a major complication of HIV disease. Its occurrence in the developing world is the subject of an interesting article by Wong et al.1 in this issue of Neurology . HAD is primarily a feature of advanced HIV disease. HAART has reduced its incidence in half; it now affects approximately 10% of patients with advanced disease. Paradoxically, in developed countries, the prevalence of HAD has increased as an unintended consequence of the very positive effects of HAART on the lifespan of HIV-infected individuals.2 That HAD even occurs in the era of HAART may be due to late commencement or to interruption of HAART or because of insufficient penetration of some HAART regimens through the blood–brain barrier3,4 or other yet-to-be-defined reasons.5 Late or intermittent use of HAART in turn is related to the lack of recognition of cognitive impairment as well as to patient/physician concerns over the potential for HAART toxicity. The recent …

Problems of management of primary congenital glaucoma in Benin City, Nigeria

To determine the problems encountered in the management of primary congenital glaucoma in developing countries. A prospective study of new patients with a diagnosis of primary congenital glaucoma attending the eye clinic of the University of Benin Teaching hospital, Benin City, Nigeria over a 5 year period, from July 2001 to June 2006. The age, sex, presenting complaints and duration were recorded. They were examined by the aid of a pen torch, hand-held slit lamp and direct ophthalmoscope. Intraocular pressure and corneal diameter were measured under anaesthesia. The patients were followed up till June 2006 and the problems encountered in management were recorded. Eight children comprising 5 males (62.5%) and 3 females (37.5%) with primary congenital glaucoma were seen. All the patients (100%) presented with buphthalmos and 7 (87.5%) had corneal opacity. Four (50%) accepted surgery but only 2 (25%) eventually had surgery. Maximum follow-up was 7 months. Presentation with features of advanced disease, poor acceptability of surgery, poor follow-up and low surgical rate are problems associated with the management of congenital glaucoma in Benin City, Nigeria.

Hypertrophic Cardiomyopathy and Symptomatic Conduction System Disease in Cardiac Amyloidosis

Cardiac involvement is the most important prognostic factor in primary amyloidosis (AL). The clinical presentation of amyloid cardiomyopathy is varied and may manifest as heart failure, brady or tachyarrhythmias, syncope, angina and rarely with features of hypertrophic cardiomyopathy and advanced symptomatic conduction system disease. The management of amyloid cardiomyopathy has always been a dilemma, as most of the drugs used in congestive heart failure are contraindicated. This report describes a 70-year-old woman who presented with syncope, severe diastolic heart failure, features of hypertrophic cardiomyopathy and severe symptomatic conduction system disease requiring a pacemaker. Amyloidosis was diagnosed on endomyocardial biopsy after abdominal fat aspirate was negative for amyloid. The patient eventually expired due to end-stage congestive heart failure.

Study protocol to investigate the effects of testosterone therapy as an adjunct to exercise rehabilitation in hypogonadal males with chronic heart failure

BackgroundTestosterone deficiency is a common occurrence in men with chronic heart failure (CHF) and may underpin features of advanced disease, including reduced skeletal muscle mass and fatigue. It is positively correlated with cardiac output and exercise capacity in patients with CHF, whereas a significant improvement in both these parameters has been observed following testosterone replacement therapy. Testosterone therapy has also been shown to reduce circulating levels of inflammatory markers, (TNF-α, sICAM-1 and sVCAM-1) in patients with established coronary artery disease and testosterone deficiency. This pilot study will assess the feasibility of a combined exercise rehabilitation and adjunctive testosterone therapy intervention for evoking improvements in exercise capacity, circulating inflammatory markers, cardiac and skeletal muscle function, indices of psychological health status and quality of life in hypogonadal males with chronic heart failure.Methods/designFollowing ethical approval, 36 patients will be randomly allocated to one of two groups: testosterone or placebo therapy during exercise rehabilitation. A combined programme of moderate intensity aerobic exercise and resistance (strength) training will be used. The primary outcome measure is exercise capacity, assessed using an incremental shuttle walk test. Secondary outcome measures include measures of peak oxygen uptake, cardiac function, lower-limb skeletal muscle contractile function and oxygenation during exercise, circulating inflammatory markers, psychological health status and quality of life.DiscussionExercise rehabilitation can safely increase exercise capacity in stable CHF patients but there is a need for studies which are aimed at evaluating the long-term effects of physical training on functional status, morbidity and mortality. This pilot study will provide valuable preliminary data on the efficacy of testosterone therapy as an adjunct to exercise rehabilitation on a range of functional, physiological and health-related outcomes in this patient population. Preliminary data will be used in the design of a large-scale randomised controlled trial, aimed at informing clinical practice with respect to optimisation of exercise rehabilitation in this patient group.

Prognostic Significance of Magnetic Resonance Imaging (MRI) of Bone Marrow (BM) in Patients with Multiple Myeloma (MM) Undergoing Treatment with High-Dose Melphalan (HDM) and Autologous Stem Cell Transplantation (ASCT).

Purpose: We have previously reported that diffuse pattern of bone marrow involvement as determined by MRI imaging of the spine, in newly diagnosed patients with MM is associated with features of advanced disease and with shorter survival compared to patients with normal, focal or variegated pattern of BM involvment. Purpose of the study was to determine the prognostic value of spinal bone MRI in the outcome of MM patients undergoing treatment with HDM and ASCT.Materials and methods: Between October 1995 and June 2006, 63 MM patients for whom a MRI of the spine before first line therapy was available, received treatment with HDM (200mg/m2 iv) and ASCT, in our Department. Four patterns of BM involvement in MRI were identified:normal pattern which required no evidence of abnormal signal,focal pattern, which consists of localized areas of abnormal marrow (on T1-weighted images, focal lesions are darker than yellow marrow and slightly darker or isointense to red marrow; on T2-weighted images they are brighter than both red and yellow marrow),diffuse pattern of abnormal marrow, where the normal bone marrow is completely replaced by the abnormal process and the intervertebral discs appear brighter or are isointense to the diseased marrow, andvariegated pattern, which consists of innumerable small foci of disease on a background of intact marrow.MRI pattern of BM involvement and multiple clinical and laboratory parameters were evaluated for their possible correlation with progression free survival (PFS) after HDM.Results: Patients' median age was 55years (range: 23 to 74 years), 60% of patients had ISS 2 or 3 before initial treatment, 54% of patients were transplanted during remission and 46% of patients had active myeloma at the time of HDM (primary refractory: 34%, resistant relapse: 12%). Nine patients (14%) had a normal MRI pattern, 33 (53%) had focal, 4 (6%) variegated and 17 (27%) diffuse MRI pattern of BM involvement. The median PFS for all patients was 20 months. Significant adverse prognostic factors for PFS included elevated creatinine and LDH serum levels, and ISS stage 3 at diagnosis. Furthermore the pattern of BM involvement by MRI correlated strongly with PFS: median PFS of 72 months for normal pattern, 20 months for focal pattern, 16 months for variegated and 9 months for diffuse pattern (p=0.016). Patients with both ISS stage 3 and diffuse MRI pattern had a median PFS of only 6 months.Conclusion: MRI of the spine before treatment provides prognostic information for the outcome of MM patients with myeloma after HDM and ASCT. Diffuse marrow replacement on MRI of the spine identifies patients with advanced MM who have a poor prognosis even after intensive therapy. Such patients are candidates for innovative treatments.

The Burden of Fatigue and Quality of Life in Myeloproliferative Disorders (MPDs): An International Internet Based Survey of 1179 MPD Patients.

Background: Scant data exists regarding the burden of fatigue and constitutional symptoms in patients with myeloproliferative disorders (MPDs) (essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis with myeloid metaplasia (MMM)).Methods: An Internet based survey of MPD patients regarding clinical course, blood counts, constitutional symptoms, and fatigue (FACT-AN and Brief Fatigue Inventory (BFI)).Results:Patient Demographics: A total of 1179 MPD patients (median age 56; 41.4% male) internationally (76% USA: 50 states, 30 countries, 6 continents) responded to the survey. Self reported diagnoses were PV (35%), ET (26%), or MMM (39%).Clinical History: 1025 patients (87%) had undergone MPD therapy (drugs 70.5%, phlebotomy 44.1%, other 16%). Thrombosis (n=261, 22%), hemorrhage (N=272; 23%), and splenomegaly (N=478 (43%) were frequently reported. Blood tests (available in 917) showed 39% were anemic, 7% transfusion dependent.Symptoms: Fatigue, pruritus, night sweats and bone pain were present across the majority of MPD patients (see table). Additionally it was observed that these symptoms appeared with nearly equal frequency in PV as in MMM patients. However MMM patients displayed more advanced features (fevers, night sweats and weight loss).MPD Associated Constitutional Symptoms in 1179 PatientsSYMPTOMPV (N=405)ET (N=304)MMM (N=456)MISSING (N=14)TOTAL (N=1179)P VALUEFatigue344 (84.9%)220 (72.4%)381 (83.6%)7945 (81.1%)<0.0001Pruritus265 (65.4%)120 (39.5%)228 (50.0%)3613 (52.6%)<0.0001Night Sweats199 (49.1%)123 (40.5%)254 (55.7%)4576 (49.4%)0.0002Bone Pain174 (43.0%)125 (41.1%)214 (46.9%)4513 (44%)0.2480Fevers53 (13.1%)26 (8.6%)81 (17.8%)2160 (13.7%)0.0013Weight Loss39 (9.6%)22 (7.2%)93 (20.4%)0154 (13.2%)<0.0001Spleen Pain17 (4.2%)27 (8.9%)30 (6.6%)474 (6.3%)<0.0001Fatigue (82% MPD linked) was significantly increased across all MPD subtypes compared to published controls for both the BFI (P<0.0001) and Fact-An (P<0.0001). Additionally 69% curtail social activity because of fatigue, 35% need assistance with activities of daily living, and 11% reported MPD associated medical disability. Fatigue strongly correlated with multiple MPD disease features including: anemia, bone pain, constitutional symptoms, pruritus, splenic pain, smoking, thrombosis, and hemorrhagic events (all p<0.0001). Interestingly, even in “asymptomatic” MPD patients (those without anemia, splenomegaly, or thrombohemorrhagic complications) (n=279)) 24% (41% PV, 31% ET, 28% MMM) described significant fatigue worse than published controls.Conclusions: Fatigue and other constitutional symptoms are a significant burden to MPD patients, despite current therapies employed. Additionally fatigue is also a significant problem even in MPD patients lacking other advanced disease features. Clearly, direct attempts to improve fatigue (through pharmacologic and non-pharmacologic interventions) are necessary.

‘Full-house’ rheumatic heart disease

We report the case and cardiac imaging of a 27 year old African female with every clinical feature of advanced rheumatic heart disease. The case illustrates the continuing life-threatening impact of rheumatic heart disease in young adults. Appropriate diagnosis and management of rheumatic heart disease in the UK remains relevant with increased immigration of at-risk populations.

Elevated cortical zinc in Alzheimer disease

To determine whether changes in brain biometals in Alzheimer disease (AD) and in normal brain tissue are tandemly associated with amyloid beta-peptide (Abeta) burden and dementia severity. The authors measured zinc, copper, iron, manganese, and aluminum and Abeta levels in postmortem neocortical tissue from patients with AD (n = 10), normal age-matched control subjects (n = 14), patients with schizophrenia (n = 26), and patients with schizophrenia with amyloid (n = 8). Severity of cognitive impairment was assessed with the Clinical Dementia Rating Scale (CDR). There was a significant, more than twofold, increase of tissue zinc in the AD-affected cortex compared with the other groups. Zinc levels increased with tissue amyloid levels. Zinc levels were significantly elevated in the most severely demented cases (CDR 4 to 5) and in cases that had an amyloid burden greater than 8 plaques/mm(2). Levels of other metals did not differ between groups. Brain zinc accumulation is a prominent feature of advanced Alzheimer disease (AD) and is biochemically linked to brain amyloid beta-peptide accumulation and dementia severity in AD.