Terry Brain

A prospective randomized, controlled trial of intravenous versus oral iron for moderate iron deficiency anaemia of pregnancy.

Abstract.  Khalafallah A, Dennis A, Bates J, Bates G, Robertson IK, Smith L, Ball MJ, Seaton D, Brain T, Rasko JEJ Launceston General Hospital (LGH), Australia; University of Tasmania, Australia; and Centenary Institute, University of Sydney, NSW, Australia) A prospective randomized, controlled trial of intravenous versus oral iron for moderate iron deficiency anaemia of pregnancy. J Intern Med 2010; 268: 286–295.

Transcriptionally Active Human Papillomavirus Is Strongly Associated With Barrett's Dysplasia and Esophageal Adenocarcinoma

OBJECTIVES:The role of human papillomavirus (HPV) in Barretts esophagus (BE) remains unclear. The few studies that have previously investigated HPV and esophageal adenocarcinoma (EAC) or BE have produced either negative data or positive results of doubtful clinical/etiological significance or have detected only low-risk HPV types. We therefore prospectively determined the prevalence of biologically active HPV in esophageal epithelium of patients representing the Barretts metaplasia–dysplasia–adenocarcinoma sequence.METHODS:HPV DNA was estimated by nested PCR and viral transcriptional activity detected by E6/7 oncogene mRNA expression and p16INK4A immunohistochemistry in fresh frozen and paraffin-embedded esophageal biopsies of patients with BE, Barretts dysplasia (BD), and EAC, as well as controls. Biopsies were obtained from the transformation zone (squamocolumnar junction (SCJ)) and the lesion, or corresponding site in controls, i.e., 2 cm above the gastroesophageal junction (GEJ).RESULTS:Of the 261 patients, 81 were positive for HPV DNA. In controls and BE, the virus was mostly detected at the transformation zone. Compared with controls (18.0%), HPV positivity was significantly more common in BD (68.6%, incidence rate ratio (IRR) 2.94, 95% confidence interval (CI) 1.78–4.85, P<0.001) and EAC (66.7%, IRR 2.87, 95% CI 1.69–4.86, P<0.001), but not in BE (22.1%, IRR 1.06, 95% CI 0.60–1.85, P=0.85). Of the patients, 92.6% were high-risk (HR) HPV, i.e., types 16 and 18. Again, p16INK4A positivity was greatest in BD and EAC and much less in BE patients (44.1%, IRR 17.0 (95% CI 4.86–59.6, P<0.001), 44.4%, 17.0 (95% CI 4.87–59.4, P<0.001), and 10.6%, 3.93 (95% CI 1.01–15.3, P=0.048) respectively). In 66 HPV DNA–positive patients tested for E6/E7 mRNA, none of the control (n=16) or BE (n=13) individuals were positive, whereas 9/22 BD and 9/15 EAC patients demonstrated oncogene expression (P<0.001). When HPV DNA, p16INK4A, and E6/E7 mRNA were all positive, there was a very strong association with disease severity (SCJ: odds ratio (OR) 104, 95% CI 20.3–529, P<0.001; lesion: OR 62.2, 95% CI 12.4–311, P<0.001) than when all were negative.CONCLUSIONS:Transcriptionally active HR-HPV was strongly associated with BD and EAC, but was largely biologically irrelevant in BE and controls, suggesting a potential role in esophageal carcinogenesis. These data provide robust justification for further detailed longitudinal, interventional, and molecular studies.

D-Dimer levels at different stages of pregnancy in Australian women: a single centre study using two different immunoturbidimetric assays.

BACKGROUND To date there is minimal data available on D-Dimer levels at different stages of pregnancy. PATIENTS AND METHODS We prospectively measured D-Dimer levels in 632 consecutive pregnant women from March 2007 to January 2009. The median age of the participants was 31 years (range; 18-42) with a median weight of 78 kilograms (range; 46-137). All subjects were investigated during each trimester with two different immunoturbidimetric assays; D-Dimer PLUS and INNOVANCE D-Dimer. D-Dimer levels were determined using a Sysmex® CA 1500 analyser. RESULTS Our data demonstrate that D-Dimer levels in pregnancy show different patterns of rise within the first trimester, depending on the assay used; D-Dimer PLUS=0.88 (SD: mean ratio), INNOVANCE D-Dimer=0.72 (SD: mean ratio). Furthermore, the rise in mean results was greater for the INNOVANCE D-Dimer assay compared to the D-Dimer PLUS assay as shown by the ratio of third to first trimester results of 3.68 and 1.96 respectively. Both D-Dimer assays demonstrated moderate levels of intra-subject variability, with overall mean CVs of 16.5% (D-Dimer PLUS) and 16.9% (INNOVANCE D-Dimer). Furthermore, we studied the association between D-Dimer levels and occurrence of diseases of pregnancy. For both assays, there was no consistently interpretable evidence of an association between raised mean D-Dimer levels or rising D-Dimer levels and any of the diseases or conditions associated with pregnancy. CONCLUSION Our data suggest that the INNOVANCE D-Dimer assay increases significantly with the advancement of pregnancy, and is more sensitive than D-Dimer PLUS assay in the pregnant population.

Glycosylated haemoglobin for screening and diagnosis of gestational diabetes mellitus

Objectives The oral glucose tolerance test (OGTT) is a cumbersome test that is time consuming, labour intensive and often poorly tolerated by pregnant women. To date, glycosylated haemoglobin (HbA1c) is the most accepted measure of chronic glycaemia outside of pregnancy. HbA1c is an uncomplicated test, less time consuming, does not require any specific patient preparation and is considered straightforward compared with the OGTT. Therefore, we prospectively tested the utility of the HbA1c when used as a screening tool in pregnancy for gestational diabetes mellitus (GDM). Settings Primary health care. Single tertiary referral centre, Tasmania, Australia. Participants A direct comparison between HbA1c levels and the OGTT results in pregnant women, tested concurrently at the 24–28 gestational week, was undertaken. A full profile of 480 pregnant women during the period from September 2012 to July 2014 was completed. Median and mean age of participants was 29 years (range 18–47 years). Interventions A simultaneous prospective assessment of HbA1c versus standard OGTT in a cohort of consecutive pregnant women presenting to our institute was performed. Results The number of women who had GDM according to OGTT criteria was 57, representing 11.9% of the evaluated 480 pregnant women. Using a cut-off value for HbA1c at 5.1% (32 mmol/mol) for detecting GDM showed sensitivity of 61% and specificity of 68% with negative predictive value (NPV) of 93%, versus sensitivity of 27% and specificity of 95% with NPV of 91% when using HbA1c cut-off value of 5.4% (36 mmol/mol). Conclusions Our results suggest that pregnant women with an HbA1c of≥5.4% (36 mmol/mol) should proceed with an OGTT. This may result in a significant reduction in the burden of testing on both patients and testing facility staff and resources. Further investigations are required to integrate and optimise the HbA1c as a single, non-fasting, screening tool for GDM. Trial registration number ACTRN12611000739910.

Effect of immunoglobulin therapy on the rate of infections in multiple myeloma patients undergoing autologous stem cell transplantation or treated with immunomodulatory agents.

Multiple myeloma (MM) is associated with a significant risk of infection due to immune dysfunction. Infections are a major cause of morbidity and mortality in MM patients. There are few data available regarding the prevalence of infection in MM patients, especially in conjunction with newer generations of immunomodulatory drugs (thalidomide, bortezomib, lenalidomide) or post autologous stem cell transplantation (ASCT). Intravenous immunoglobulin (IVIG) has been used successfully to reduce infection rates in the stable phase of MM, with limited data in other stages. We retrospectively analyzed 47 patients with MM from March 2006 to June 2009 at our institution. All patients received thalidomide and steroid therapy for at least 6 months. Nine patients received bortezomib and 11 lenalidomide subsequent to thalidomide, because of disease progression, and 22 patients underwent ASCT. The median age was 64 years (range 37–86), with a female–to-male ratio of 18:29. The median residual-serum IgG-level at time of infection was 3.2 g/L, IgA 0.3 g/L and IgM 0.2 g/L. Most patients suffered from recurrent moderate to severe bacterial infections, including the ASCT group. Fifteen patients suffered from different degrees of viral infections. All patients except 3 received IVIG therapy with a significant decline of the rate of infection thereafter (p<001). Our analysis shows that patients with MM treated with the new immunomodulatory drugs in conjunction with steroids are at significant increased risk of infection. Employing IVIG therapy appears to be an effective strategy to prevent infection in this cohort of patients. Further studies to confirm these findings are warranted.

Evaluation of the Innovance d-Dimer Assay for the Diagnosis of Disseminated Intravascular Coagulopathy in Different Clinical Settings

Disseminated intravascular coagulopathy (DIC) is a serious disease with fatal consequences. We prospectively analyzed Innovance d-dimer immunoturbidimetric assay in 68 patients diagnosed with DIC on the background of malignancy (22), severe infection (20), or multitrauma (26) at a single institution between January 2010 and January 2011. Median age was 61 years (range 20-89). All patients were assessed according to the International Society of Thrombosis and Haemostasis (ISTH) DIC score. Applying a threshold of Innovance d-dimer of 10 mg/L fibrinogen equivalent unit (normal <0.5) was correlated with the highest sensitivity in malignancy (86%) and trauma/surgery (80%) compared to 54% in infection. The specificity remained high at 97% in infection, 81% in trauma and 77% in malignancy with a negative predictive value of 97% in trauma and malignancy, and 88% in infection. Our data suggest that Innovance d-dimer is a useful and simple tool that enhances the ISTH DIC diagnostic criteria. Further studies to confirm these findings are warranted.

Characterisation of colonic dysplasia-like epithelial atypia in murine colitis

AIM To determine if exacerbation of pre-existing chronic colitis in Winnie (Muc2 mutant) mice induces colonic dysplasia. METHODS Winnie mice and C57BL6 as a genotype control, were administered 1% w/v dextran sulphate sodium (DSS) orally, followed by drinking water alone in week-long cycles for a total of three cycles. After the third cycle, mice were killed and colonic tissue collected for histological and immunohistochemical evaluation. Inflammation and severity of dysplasia in the colonic mucosa were assessed in H&E sections of the colon. Epithelial cell proliferation was assessed using Ki67 and aberrant β-catenin signalling assessed with enzyme-based immunohistochemistry. Extracted RNA from colonic segments was used for the analysis of gene expression using real-time quantitative PCR. Finally, the distribution of Cxcl5 was visualised using immunohistochemistry. RESULTS Compared to controls, Winnie mice exposed to three cycles of DSS displayed inflammation mostly confined to the distal-mid colon with extensive mucosal hyperplasia and regenerative atypia resembling epithelial dysplasia. Dysplasia-like changes were observed in 100% of Winnie mice exposed to DSS, with 55% of these animals displaying changes similar to high-grade dysplasia, whereas high-grade changes were absent in wild-type mice. Occasional penetration of the muscularis mucosae by atypical crypts was observed in 27% of Winnie mice after DSS. Atypical crypts however displayed no evidence of oncogenic nuclear β-catenin accumulation, regardless of histological severity. Expression of Cav1, Trp53 was differentially regulated in the distal colon of Winnie relative to wild-type mice. Expression of Myc and Ccl5 was increased by DSS treatment in Winnie only. Furthermore, increased Ccl5 expression correlated with increased complexity in abnormal crypts. While no overall difference in Cxcl5 mucosal expression was observed between treatment groups, epithelial Cxcl5 protein appeared to be diminished in the atypical epithelium. CONCLUSION Alterations to the expression of Cav1, Ccl5, Myc and Trp53 in the chronically inflamed Winnie colon may influence the transition to dysplasia.

An open-labelled, randomized, cross-over study of the effect of electromechanical pumps versus conventional gravity flow on platelet transfusion in adult haematology patients

Background: Only few data are available regarding the effect of the method of platelet transfusion on the platelet increment. Although administering platelets via either a free-flowing gravity or an electromechanical pump is common practice, there are no randomized trials addressing differences between these techniques. Objectives: Our study aimed to determine whether infusion methods influence the platelet increment. Methods: We studied the effect of 3 different electromechanical pumps that are used routinely for transfusion at our hospital; the Graseby 3000, Imed Gemini PC-1, and the Baxter Colleague in comparison to the free-flow gravity method. Between January 2007 and January 2011, we prospectively randomized the platelet transfusion method for 35 patients, in total 171 transfusion episodes. Most of the patients received platelets by each of the 4 different techniques. Patients with factors that may have influenced platelet recovery, such as infection, coagulopathy, platelet or HLA antibodies, were excluded. Results: The Baxter Colleague pump method was associated with the highest platelet increment at 1 h after transfusion (p = 0.03). This effect vanished after 24 h. The Gemini and Graseby pumps gave results similar to those of the gravity flow method. Conclusion: None of the different infusion pumps were inferior to the gravity flow method. Further studies to confirm these findings are warranted.

Multifocal primary bone lymphoma: durable complete remission after R-CHOP chemotherapy

Primary bone lymphoma (PBL) is a type of non-Hodgkins lymphoma predominantly affecting the skeletal system. PBL is an extremely rare cancer in adults affecting mainly the axial skeleton. The extent of bone involvement in these patients is variable. Most of the cases reported had single or a few skeletal lesions. We report a patient who had extensive multifocal lymphoma involving the axial skeleton and a very good and durable response to R-CHOP chemotherapy.

Application of Massive Transfusion Protocol is Associated with a Low Incidence of Coagulopathy and Mortality Rate

Background: Massive haemorrhage and subsequent Massive Transfusion (MT) are associated with serious, often fatal complications including intractable Disseminated Intravascular Coagulation (DIC). Historically undesirable outcomes demonstrate the need to improve the management approach of MT. It is clear that evidence-based guidelines and protocols should be developed with the aim of improving MT-outcome. Methods: We implemented an evidence-based MT-Protocol (MTP) in 2007 and studied all patients (105) from Jan 2008 to Jan 2011 who required MT and were treated with the MTP at our institution. The MTP includes two phases and incorporates a fixed volume of Fresh Frozen Plasma (FFP), cryoprecipitate and platelets in addition to Packed Red Blood Cells (PRBC). Results: The median age of patients was 57 years (range, 18-86). The male to female ratio was 74:31. Median Hb was 90 g/L (range, 44-110) and platelet count was 190/nl (range, 34-817). Thirteen patients developed mild DIC; 22 moderate DIC and one severe DIC. D-dimer showed average increase of 7.9 mg/L with a range between 0.6-35 mg/L (Normal <0.5). Average INR was 1.97, (range, 1.2-7.2), while average APTT was 36 seconds (range, 22-88s). The mortality rate was 11.4% (12/105) and these were mainly related to underlying trauma rather than DIC with the exception of 1 patient. The average number of transfused PRBC was 15 units (range, 6-42); cryoprecipitate, 20(range, 10-60); platelets, 2(range, 1-7) and FFP, 8(range, 2-20). Conclusion: Despite serious bleeding secondary to trauma or surgery, the implementation of MTP seems to have reduced the occurrence of severe DIC and was associated with a relatively low mortality-rate. Further studies to confirm these findings are warranted.