Pre-Operative Embolisation of Musculoskeletal Tumours - A Single Centre Experience.

INTRODUCTION: The management of musculoskeletal tumours is complex and requires a multi-disciplinary approach. Preoperative embolisation can be often employed to reduce intra-operative blood loss and complication rates from surgery. We report our experience with the safety, technical success and efficacy of pre-operative embolisation in musculoskeletal tumours. MATERIALS AND METHODS: Thirteen consecutive patients who underwent pre-operative embolisation of a musculoskeletal tumour followed by surgical intervention at our institution from May 2012 to January 2016 were enrolled into the study. Patient demographics, tumour characteristics, embolisation techniques and type of surgery were recorded. Technical success of embolisation, amount of blood loss during surgery and transfusion requirements were estimated. RESULTS: There were five female and eight male patients who underwent pre-operative embolisation during the study period. The age ranged between 16 to 68 years, and the median age was 54. Technical success was achieved in all patients. Mean intra-operative blood loss was 1403ml, with a range of 150ml to 6900ml. Eight patients (62%) required intra-operative blood products of packed red blood cells and fresh frozen plasma. No major complications occurred during embolisation. CONCLUSION: Pre-operative trans-arterial embolisation is feasible and safe for a variety of large and hypervascular musculoskeletal tumours. Our small series suggests that preoperative embolisation could contribute to the reduction of the intra-operative and post-operative blood product transfusion. It should be considered as a pre-operative adjunct for major tumour resections with a high risk of bleeding. The use of the haemoglobin gap complemented the assessment of perioperative blood loss.

Phase II trial of dasatinib for recurrent or metastatic c-KIT expressing adenoid cystic carcinoma and for nonadenoid cystic malignant salivary tumors.

BACKGROUND: Adenoid cystic carcinoma (ACC) is a subtype of malignant salivary gland tumors (MSGT), in which 90% of cases express cKIT. Dasatinib is a potent and selective inhibitor of five oncogenic protein tyrosine kinases (PTKs)/kinase families including cKIT. We conducted a phase II study to determine the antitumor activity of dasatinib in ACC and non-ACC MSGT. PATIENTS AND METHODS: In a two-stage design, patients with progressive, recurrent/metastatic ACC (+cKIT) and non-ACC MSGT (separate cohort) were treated with dasatinib 70 mg p.o. b.i.d. Response was assessed every 8 weeks using RECIST. RESULTS: Of 54 patients: 40 ACC, 14 non-ACC (1, ineligible excluded); M:F = 28 : 26, median age 56 years (range 20-82 years), ECOG performance status 0 : 1 : 2 = 24 : 28 : 2, prior radiation: 44, prior chemotherapy: 21. The most frequent adverse events (AEs) (as % of patients, worst grade 2 or higher) were: fatigue (28%), nausea (19%), headache (15%), lymphopenia (7%), dyspnea (11%), alanine aminotransferase increased (7%), anorexia (7%), vomiting (7%), alkaline phosphatase increased (6%), diarrhea (6%), neutropenia (6%), and noncardiac chest pain (6%). No grade 4 AE occurred, 15 patients experienced a grade 3 AE, primarily dyspnea (5) and fatigue (4), and cardiac toxicity (1 prolonged QTc). Among ACC patients, best response to dasatinib: 1 patient (2.5%) had partial response, 20 patients (50%) had stable disease (SD) (3-14 months), 12 patients (30%) had PD, 2 withdrew, 3 discontinued therapy due to AE, and 2 died before cycle 2. Median progression-free survival was 4.8 months. Median overall survival was 14.5 months. For 14 assessable non-ACC patients, none had objective response, triggering early stopping rule. Seven had SD (range 1-7 months), 4 PD, 2 discontinued therapy due to AE, and 1 died before cycle 2. CONCLUSION: Although there was only one objective response, dasatinib is well tolerated, with tumor stabilization achieved by 50% of ACC patients. Dasatinib demonstrated no activity in non-ACC MSGT.

Depression, anxiety and stress among patients with diabetes in primary care: A cross-sectional study.

BACKGROUND: The incidence of diabetes mellitus is ever increasing. Individuals with diabetes mellitus may have concurrent mental health disorders and are shown to have poorer disease outcomes. The objectives of this study were to determine the prevalence of depression, anxiety and stress (DAS) in diabetes patients aged 20 years or more in the primary care setting. METHODS: This was a cross-sectional study involving the use of self-administered questionnaire conducted in eight primary care private and government clinics in Pulau Pinang and Melaka, Malaysia. The validated DASS-21 questionnaire was used as a screening tool for the symptoms of DAS. Prior permission was obtained from the patients and, clearance from ethical committee was obtained before the start of the study. Data analysis was done using SPSS statistical software. RESULTS: A total of 320 patients with diabetes from eight centres were enrolled via convenience sampling. Sample size was calculated using the Kish's formula. The prevalence of DAS among patients with diabetes from our study was 26.6%, 40% and 19.4%, respectively. Depression was found to be significantly associated with marital status and family history of DAS; anxiety was significantly associated with monthly household income, presence of co-morbidities and family history of DAS; and stress was significantly associated with occupation and family history of DAS. CONCLUSION: The prevalence of DAS was higher in patients with diabetes compared with the general community. We recommend to routinely screen all patients with diabetes using the DASS-21 questionnaire because it is easy to perform and inexpensive.

Systolic-diastolic coupling of myocardial deformation of the left ventricle in children with left ventricular noncompaction.

Disruption of the myocardial architecture in left ventricular noncompaction (LVNC) may alter myocardial deformation. We evaluated LV myocardial deformation and tested the hypothesis that tight systolic-diastolic coupling occurs in LVNC. Longitudinal and circumferential strain and strain rates (SRs) as determined by speckle tracking echocardiography in nine children aged 5.6 ± 5.5 years was compared with those in nine controls. Left ventricular systolic myocardial deformation parameters were correlated with ejection fraction and indices of diastolic deformation. Compared with controls, patients had lower global LV systolic longitudinal strain (P = 0.008), systolic SR (P = 0.05) and early diastolic SR (P < 0.001). Similarly, LV systolic circumferential strain (base, P = 0.04; papillary muscle level, P = 0.01; apex, P = 0.04), systolic SR (base, P = 0.04) and early diastolic SR (papillary muscle level, P = 0.004, apex, P = 0.02) were lower in patients than in controls. Among patients, the LV ejection fraction correlated with global longitudinal systolic strain and SR and circumferential systolic strain and SR at all levels (all P < 0.05). Positive correlations existed between early diastolic and systolic SRs in corresponding dimensions (longitudinal r = 0.80, P = 0.01; circumferential at base, r = 0.91, P = 0.001; papillary muscle level, r = 0.96, P < 0.001; apex r = 0.98, P = <0.001). In conclusion, LV myocardial deformation is reduced in the longitudinal and circumferential dimensions and manifests tight systolic-diastolic coupling in children with LVNC.

Relationship between carotid intima-media thickness and arterial stiffness in children after Kawasaki disease.

BACKGROUND: Evidence of premature atherosclerosis and systemic arterial stiffening in patients after Kawasaki disease is accumulating. AIM: To test the hypothesis that carotid intima-media thickness (IMT), a surrogate marker of atherosclerosis, is associated with systemic arterial stiffness in children after Kawasaki disease. METHODS: A cohort of 72 patients was studied, comprising 26 patients with Kawasaki disease and coronary aneurysms (group I), 24 patients with Kawasaki disease and normal coronary arteries (group II) and 22 healthy age-matched children (group III). The carotid IMT, carotid artery stiffness index, brachioradial pulse wave velocity (PWV), fasting total cholesterol, high-density lipoprotein (HDL) cholesterol and low-density lipoprotein (LDL) cholesterol were determined and compared among the three groups. RESULTS: The carotid IMT was related to indices of arterial stiffness, and significant determinants of carotid IMT were identified by multivariate analysis. The mean (standard deviation (SD)) carotid IMT of both group I (0.41 (0.04) mm) and group II (0.39 (0.04) mm) was significantly greater than that of group III (0.36 (0.04) mm; p<0.001 and p = 0.008, respectively). For the entire cohort, carotid IMT correlated positively with LDL cholesterol (r = 0.31, p = 0.009), carotid artery stiffness index (r = 0.40, p = 0.001) and brachioradial PWV (r = 0.28, p = 0.016), but not with age, body mass index, systemic blood pressure, and HDL and total cholesterol. Multiple linear regression analysis identified carotid artery stiffness index (beta = 0.25, p = 0.028) and subject grouping (beta = -0.39, p = 0.001; model R(2) = 0.29) as significant correlates of carotid IMT. CONCLUSION: The increased carotid IMT in children after Kawasaki disease is associated with systemic arterial stiffening.

Central and peripheral arterial stiffness in patients after surgical repair of tetralogy of Fallot: implications for aortic root dilatation.

OBJECTIVES: To test the hypotheses that (1) the central conduit arteries stiffen preferentially over the peripheral conduit arteries in patients with repaired tetralogy of Fallot (ToF); and (2) central arterial stiffening is related to aortic root dilatation. DESIGN AND PATIENTS: Heart-femoral pulse wave velocity (PWV), femoral-ankle PWV, carotid augmentation index and body surface area-adjusted aortic sinotubular dimension were determined in 31 children after ToF repair and compared with those in 31 age-matched controls after left-to-right shunt repair. In addition, the PWVs and augmentation index were related to the sinotubular junction dimension. SETTINGS: Tertiary paediatric cardiac centre. RESULTS: Compared with controls, patients had significantly greater heart-femoral PWV (mean 666 (SD 151) v 587 (81) cm/s, p = 0.021) and carotid augmentation index (-14.1 (17.0)% v -25.2 (14.6)%, p = 0.016), whereas the right (888 (202) v 845 (207) cm/s, p = 0.42) and left (918 (227) v 851 (215) cm/s, p = 0.25) femoral-ankle PWVs were similar between the two groups. The sinotubular junction z score of patients was significantly greater than that of controls (4.7 (1.5) v 1.1 (1.4), p < 0.001). Univariate analysis showed that the sinotubular junction z score correlated positively with heart-femoral PWV (r = 0.43, p = 0.001) and carotid augmentation index (r = 0.46, p = 0.001). Multiple linear regression similarly identified heart-femoral PWV (beta = 0.30, p = 0.04) and carotid augmentation index (beta = 0.31, p = 0.04) (model R(2) = 0.26) as significant determinants of sinotubular junction z score. CONCLUSIONS: The aorta stiffens in patients with repaired ToF, which may contribute to progressive dilatation of the aortic root in the long term.

Expression of multiple outer membrane protein sequence variants from a single genomic locus of Anaplasma phagocytophilum.

Anaplasma phagocytophilum is the causative agent of an emerging tick-borne zoonosis in the United States and Europe. The organism causes a febrile illness accompanied by other nonspecific symptoms and can be fatal, especially if treatment is delayed. Persistence of A. phagocytophilum within mammalian reservoir hosts is important for ensuring continued disease transmission. In the related organism Anaplasma marginale, persistence is associated with antigenic variation of the immunoprotective outer membrane protein MSP2. Extensive diversity of MSP2 is achieved by combinatorial gene conversion of a genomic expression site by truncated pseudogenes. The major outer membrane protein of A. phagocytophilum, MSP2(P44), is homologous to MSP2 of A. marginale, has a similar organization of conserved and variable regions, and is also encoded by a multigene family containing some truncated gene copies. This suggests that the two organisms could use similar mechanisms to generate diversity in outer membrane proteins from their small genomes. We define here a genomic expression site for MSP2(P44) in A. phagocytophilum. As in A. marginale, the msp2(p44) gene in this expression site is polymorphic in all populations of organisms we have examined, whether organisms are obtained from in vitro culture in human HL-60 cells, from culture in the tick cell line ISE6, or from infected human blood. Changes in culture conditions were found to favor the growth and predominance of certain msp2(p44) variants. Insertions, deletions, and substitutions in the region of the genomic expression site encoding the central hypervariable region matched sequence polymorphisms in msp2(p44) mRNA. These data suggest that, similarly to A. marginale, A. phagocytophilum uses combinatorial mechanisms to generate a large array of outer membrane protein variants. Such gene polymorphism has profound implications for the design of vaccines, diagnostic tests, and therapy.

Initial seizure threshold of bilateral electroconvulsive therapy in Chinese.

INTRODUCTION: This preliminary study examined the initial seizure threshold for bilateral electroconvulsive therapy (ECT) in Chinese and the correlates of this seizure threshold. METHOD: Fifty-four patients underwent stimulus dose titration in a standardized protocol. RESULTS: The mean initial seizure threshold was 117 mC (range 48-403 mC). Stepwise regression analysis showed that age, body mass index, and gender were independently related to seizure threshold and accounted for 36, 7, and 6% of its variance, respectively. Determination of a relationship between gender and seizure threshold was limited by the higher starting electrical dosage in men. DISCUSSION: This preliminary study suggests that the seizure threshold for bilateral ECT in Chinese is comparable with that in the Western population. Our finding that body mass index is related to seizure threshold has not been reported previously. We also propose several differences between bilateral and unilateral ECT in the determinants of seizure threshold.

Inhibition of malignant cell growth by 311, a novel iron chelator of the pyridoxal isonicotinoyl hydrazone class: effect on the R2 subunit of ribonucleotide reductase.

The key roles of iron and iron proteins in cell proliferation make them potential targets for cancer therapy. However, clinical trials directed toward perturbation of tumor iron homeostasis by iron chelation have been limited to the use of deferoxamine (DFO). There is thus a need to develop agents with greater efficacy. In the present study, we investigated the mechanism of cytotoxicity of 311 (2-hydroxy-1-naphthylaldehyde benzoyl hydrazone), a novel iron chelator of the pyridoxal isonicotinoyl class. We found that 311 inhibited the growth of CCRF-CEM cells in a time- and concentration-dependent fashion with an IC(50) that was approximately 20-fold lower than that of DFO. 311 also inhibited the growth of breast, bladder, and head and neck cancer cell lines. Using electron spin resonance (ESR) spectroscopy analysis, we found that a 12-h exposure of CCRF-CEM cells to 311 inhibited the tyrosyl radical ESR signal of the R2 subunit of ribonucleotide reductase. However, overproduction of the R2 subunit in hydroxyurea-resistant CCRF-CEM cells was associated with a decrease in sensitivity of cells to 311 but not to DFO. Our studies show that 311 is a more potent cytotoxic agent than DFO, with activity against both hematopoietic and nonhematopoietic cell lines regardless of their p53 status. Furthermore, the ESR studies suggest that inhibition of the R2 subunit of ribonucleotide reductase is at least one mechanism by which 311 blocks cell proliferation.

Immunization of mice against West Nile virus with recombinant envelope protein.

West Nile (WN) virus is a mosquito-borne flavivirus that emerged in the United States in 1999 and can cause fatal encephalitis. Envelope (E) protein cDNA from a WN virus isolate recovered from Culex pipiens in Connecticut was expressed in Escherichia coli. The recombinant E protein was purified and used as Ag in immunoblot assays and immunization experiments. Patients with WN virus infection had Abs that recognized the recombinant E protein. C3H/HeN mice immunized with E protein developed E protein Abs and were protected from infection with WN virus. Passive administration of E protein antisera was also sufficient to afford immunity. E protein is a candidate vaccine to prevent WN virus infection.

Influenza A among patients with human immunodeficiency virus: an outbreak of infection at a residential facility in New York City.

Although annual influenza vaccination is recommended for persons who are infected with human immunodeficiency virus (HIV), data are limited regarding the epidemiology of influenza or the effectiveness of influenza vaccination in this population. We investigated a 1996 outbreak of infection with influenza A at a residential facility for persons with AIDS. We interviewed 118 residents and employees, reviewed 65 resident medical records, and collected serum samples for measurement of influenza antibody titers. After controlling for history of smoking, influenza vaccination, and resident or employee status, in a multivariate model, HIV infection was not statistically associated with influenza-like illness (ILI). Symptoms and duration of ILI were similar for most HIV-infected and HIV-uninfected persons. However, 8 (21.1%) of 38 HIV-infected persons with ILI (vs. none of 15 HIV-uninfected persons) were either hospitalized, evaluated in an emergency room, or had ILI lasting > or = 14 days (P=.06). Vaccination effectiveness (VE) was similar for HIV-infected and HIV-uninfected persons. Vaccination was most effective among HIV-infected persons with CD4 cell counts of >100 cells/microL (VE, 65%; 95% CI, 36%--81%) or HIV type 1 virus load of <30,000 copies/mL (VE, 52%; 95% CI, 11%--75%). Providers should continue to offer influenza vaccination to HIV-infected persons.

Stimulus dose titration for electroconvulsive therapy.

UNLABELLED: Stimulus dose titration for electroconvulsive therapy (ECT), the method to determine seizure threshold accurately, has not been commonly practiced. We describe our early experience of dose titration in 22 Chinese patients and compare seizure thresholds measured by dose titration with values predicted by the formula-based 'half-age' METHOD: Seizure thresholds, as measured by dose titration, varied fourfold among our sample and the average value was 105.5 mC or 16.7 J. At the titration session, 27% of patients had seizures after a single stimulation and 37% had seizures after two stimulations. Only one patient required four stimulations to induce a seizure. No patient had significant adverse events associated with the dose titration procedure. The 'half-age' method in average overestimated seizure thresholds by 44% when compared with that measured by dose titration and in 23% of our sample, the overestimation was more than 100%. The pros and cons of dose titration and 'half-age' prediction method will be discussed. Our early experience suggests that dose titration could be performed in the majority of patients receiving ECT.

An outbreak of Legionella micdadei pneumonia in transplant patients: evaluation, molecular epidemiology, and control.

PURPOSE: To describe a nosocomial outbreak of Legionella micdadei pneumonia in transplant patients and to characterize the source of the outbreak and the control measures utilized. SUBJECTS AND METHODS: We performed retrospective Legionella micdadei serologic testing to enhance case finding in transplant patients with pneumonia that lacked a documented microbial etiology, as well as prospective environmental surveillance of water sites and testing for Legionella in clinical specimens. RESULTS: During a 3-month period, 12 cases of Legionella micdadei pneumonia were identified either by culture or serologic testing among 38 renal and cardiac transplant patients. Legionella micdadei isolates from hot water sources were found by pulsed-field gel electrophoresis to have a DNA banding pattern that was identical to the isolates from the first 3 culture-positive cases and from 2 cases that occurred 16 months later. CONCLUSIONS: Hospitals caring for organ transplant recipients and other immunosuppressed patients must be aware of the possibility of environmental sources of outbreaks of Legionella infection. A first-line screen with the Legionella urine antigen test will identify Legionella pneumophila serogroup 1. However, specific cultures in outbreak situations should be considered to identify other Legionella pneumophila serotypes and the nonpneumophila Legionella species.

Expression of a gene encoding the major antigenic protein 2 homolog of ehrlichia chaffeensis and potential application for serodiagnosis.

The major antigenic protein 2 (MAP2) homolog of Ehrlichia chaffeensis was cloned and expressed. The recombinant protein was characterized and tested in an enzyme-linked immunosorbent assay (ELISA) format for potential application in the serodiagnosis of human monocytic ehrlichiosis. The recombinant protein, which contained a C-terminal polyhistidine tag, had a molecular mass of approximately 26 kDa. The antigen was clearly identified by Western immunoblotting using antihistidine antibody. However, immune sera failed to react with the recombinant on immunoblots when the antigen was denatured by heat or reduced using beta-mercaptoethanol. The recombinant MAP2 (rMAP2) was used in an ELISA format with 60 blinded serum samples. Twenty of the serum samples were previously demonstrated to contain antibodies reactive with E. chaffeensis by indirect immunofluorescence assays (IFAs). The remaining 40 samples were seronegative. All samples negative by IFA were also found to be negative for antibodies against the rMAP2 of E. chaffeensis by using the ELISA. Only 1 of 20 IFA-positive samples tested negative in the rMAP2 ELISA. There was 100% agreement using IFA-negative samples and 95% agreement using IFA-positive samples, resulting in a 97.5% overall agreement between the two assays. These data suggest that the rMAP2 homolog of E. chaffeensis may have potential as a test antigen for the serodiagnosis of human monocytic ehrlichiosis. To our knowledge, this recombinant is unique because it is thus far the only E. chaffeensis recombinant antigen that has been shown to work in an ELISA format.

Transfusion-associated transmission of babesiosis in New York State.

BACKGROUND: Babesiosis can be life-threatening in immunocompromised individuals. Although the disease is usually transmitted by tick bite, more than 20 cases have been reported of infection transmitted by transfusion of blood or blood components obtained from apparently healthy donors from endemic areas in the United States. This report describes several recent cases of transfusion-transmitted babesiosis in New York State. STUDY DESIGN AND METHODS: Transfusion-associated incidents of babesiosis infection were identified and investigated. Seroprevalence of babesiosis in healthy blood donors in a highly endemic area was ascertained. RESULTS: In three incidents, babesiosis was diagnosed in five of eight patients given infected blood: two premature infants, an elderly patient with gastrointestinal bleeding, and two patients with thalassemia. Seroprevalence in blood donors on Shelter Island (Suffolk County, eastern Long Island), a highly endemic area, was 4.3 percent in May 1998. CONCLUSIONS: Infected donors lived in endemic areas and were asymptomatic with no history of tick bite. Blood collected in January 1997 from one donor was infectious. Those transfusion recipients who were infected were neonatal, elderly, or chronically transfused patients. Babesiosis should be included in the differential diagnosis of febrile illness in immunocompromised recipients of blood transfusion, particularly in the Northeastern United States.

Increased sensitivity of hydroxyurea-resistant leukemic cells to gemcitabine.

Tumor cell resistance to certain chemotherapeutic agents may result in cross-resistance to related antineoplastic agents. To study cross-resistance among inhibitors of ribonucleotide reductase, we developed hydroxyurea-resistant (HU-R) CCRF-CEM cells. These cells were 6-fold more resistant to hydroxyurea than the parent hydroxyurea-sensitive (HU-S) cell line and displayed an increase in the mRNA and protein of the R2 subunit of ribonucleotide reductase. We examined whether HU-R cells were cross-resistant to gemcitabine, a drug that blocks cell proliferation by inhibiting ribonucleotide reductase and incorporating itself into DNA. Contrary to our expectation, HU-R cells had an increased sensitivity to gemcitabine. The IC50 of gemcitabine was 0.061 +/- 0.03 microM for HU-R cells versus 0.16 +/- 0.02 microM for HU-S cells (P = 0.005). The cellular uptake of [3H]gemcitabine and its incorporation into DNA were increased in HU-R cells. Over an 18-h incubation with radiolabeled gemcitabine (0.25 microM), gemcitabine uptake was 286 +/- 37.3 fmol/10(6) cells for HU-R cells and 128 +/- 8.8 fmol/10(6) cells for HU-S cells (P = 0.03). The incorporation of gemcitabine into DNA was 75 +/- 6.7 fmol/10(6) cells for HU-R cells versus 22 +/- 0.6 fmol/10(6) cells for HU-S cells (P < 0.02). Our studies suggest that the increased sensitivity of HU-R cells to gemcitabine results from increased drug uptake by these cells. This, in turn, favors the incorporation of gemcitabine into DNA, resulting in enhanced cytotoxicity. The increased sensitivity of malignant cells to gemcitabine after the development of hydroxyurea resistance may be relevant to the design of chemotherapeutic trials with these drugs.