Spontaneous venous thromboembolism (VTE) may represent the first manifestation of previously undiagnosed malignancy; however, contemporary international guidelines call for a limited approach to screening for malignancy in such patients. This retrospective cohort study of 328 patients presenting to the Auckland City Hospital Thrombosis Unit identified 17 patients who were subsequently diagnosed with some form of malignancy within 12 months of their presentation. Review of their history, physical examination and limited age and gender-appropriate cancer screening investigations as described by the National Institute for Clinical Excellence and International Society of Thrombosis and Haemostasis guidelines revealed that all 17 would have been safely diagnosed by the 'limited' screening approach endorsed by these guidelines, thus presenting a 'real-world' basis for clinicians to pursue 'limited' screening for malignancy in their everyday practice in patients with spontaneous VTE.

Rivaroxaban is used increasingly as an oral anticoagulant; however, a specific reversal agent is not currently available in the Australasian setting. There is also variation across international consensus guidelines regarding advice on the management of bleeding.

Obesity represents a significant public health problem across the developed world. Bariatric surgery is considered the most effective treatment option for morbidly obese individuals in whom non-surgical weight loss has proved unsuccessful, reflecting large-scale Swedish prospective cohort study data demonstrating superior reductions in related morbidity and all-cause mortality compared with conventional weight loss management.1 The laparoscopic Roux-en-Y gastric bypass (LRYGB) is the bariatric operation associated with a greater proportion of excess weight lost compared to the more popular gastric sleeve based on several large prospective, randomised trials.2-4 Dabigatran is thought to be absorbed in the lower stomach and duodenum based on the relatively rapid time to achieve peak serum levels in the serum.5 This is precisely the absorptive surface excluded from the gastrointestinal (GI) tract by the LRYGB operation. While there is no established therapeutic range, data from the Phase II PETRO study (ClinicalTrials.gov Identifier: NCT01227629) showed a mean (range) peak of 184 (64–443) ng/ml and mean trough of 90 (31–225) ng/ml, both based on 150 mg twice daily dosage.6 In 2017, we opportunistically observed a very low peak serum dabigatran of 11 ng/ml in a 46-year-old woman who had undergone LRYGB surgery for weight loss and management of Type II diabetes. Her preoperative peak level measured 8 months earlier was 160 ng/ml, closely approximating the mean peak observed in the PETRO study. Our patient was safely converted to warfarin without experiencing any clinically apparent breakthrough thrombotic events; however, her case prompted the question of whether her very low dabigatran concentration reflected GI malabsorption due to changes in anatomy following LRYGB surgery. As dabigatran remains the most commonly prescribed direct oral anticoagulant (DOAC) in New Zealand (NZ), we were also concerned that other patients on dabigatran therapy may also have sub-therapeutic concentrations following LRYGB, therefore exposing them to a risk of future thrombotic events. There are limited data on oral anticoagulation following bariatric surgery. Case reports of thromboembolic events following LRYGB-type surgery include cerebral infarcts and a saddle pulmonary embolism.7-9 We carried out a retrospective case series of patients who underwent LRYGB surgery at Auckland City (ACH), Middlemore (MMH) and North Shore (NSH) Hospitals between 1 July 2011 (the date dabigatran was first licensed for use in NZ) and 31 December 2018. Electronic dispensing records of those patients who had undergone LRYGB at each hospital were interrogated to identify those prescribed dabigatran. These patients were asked to attend their local community laboratory and undergo measurement of a peak serum dabigatran concentration, dilute thrombin clotting time (dTCT) and serum creatinine. A peak was defined as the serum concentration between 0·5 and 3 h post-dose, consistent with the PETRO and RE-LY (ClinicalTrials.gov Identifier: NCT00262600) studies.6, 10 The dTCT assay was performed on the STA-R Analyser (Diagnostica Stago, Asi è res sur Seine, France) using citrated patient plasma samples diluted 1:8 in Owren-Koller buffer and mixed with normal plasma, followed by the addition of excess human thrombin reagent (1·5 NIH units thrombin/ml). The time to formation of a fibrin clot was then measured using a viscosity-based detection system. Dabigatran concentrations were calculated from this using a 4-point calibration curve (Hyphen BioMed, Neuvillesur-Oise, France).11 Relevant data of 453 patients who underwent LRYGB surgery across the study period were obtained, comprising 187 at ACH, 149 at NSH and 11 at MMH. Of these, nine were identified as being on dabigatran at the time of study and gave their consent to participate. The results from these nine participants are presented in Table I. The median (range) peak serum dabigatran concentration was 34·6 (10–64) ng/ml and median peak dTCT was 67·5 s. Two patients had additional trough measurements of 17 and 28 ng/ml. The median (range) time from surgery to measurement of dabigatran concentration was 876 (25–2062) days. No clinical thromboembolic events were reported during the study period and no patients were identified to be concurrently taking other medications known to potentially interact with dabigatran. Creatinine, μmol/l These results represent the largest series of serum dabigatran following LRYGB surgery published to date. They demonstrate markedly and consistently reduced concentrations relative to Phase II trial data, with the highest values in our cohort only coinciding with the fifth centile reported in the PETRO dataset. This suggests absorption may either be impaired or delayed in the setting of altered GI tract anatomy following the LRYGB, and raises significant concern regarding the risk of future thromboembolic events, which is supported by the aforementioned case reports. Further work is required to evaluate the exact pharmacokinetic profile of dabigatran in this setting. Limited data on dabigatran absorption following bariatric surgery are available in the literature. A recent case series of DOAC serum concentrations in post-bariatric surgery patients demonstrated dabigatran levels within the normal expected range in two patients who had undergone gastric sleeve procedures. However, unlike the LRGYB, this operation retains the area of the GI tract responsible for dabigatran absorption.12 Additionally, an earlier published review of case reports describing low serum dabigatran concentrations from the World Health Organization (WHO) Global Database of Individual Case Safety Reports ('VigiBase') included two patients who had undergone gastric bypass surgery and one with short gut syndrome, supporting our observations described here. Of note, five of the patients contained in this analysis have since been switched to the alternative DOAC, rivaroxaban, and peak serum concentrations were also obtained on these patients. The median (range) was 174 (80–264) ng/ml, which is comparable to the median (range) of 124·6 (91·4–195·5) ng/ml reported previously in the literature across two Phase IIb trials of this medication.13 Recent international guidance suggests warfarin is the oral anticoagulant of choice after bariatric surgery given its ability to be monitored and dose-adjusted.5 Our present data imply significant caution should be exercised with the use of dabigatran after LRYGB, and obtaining drugs concentrations both before and after surgery to assess for possible malabsorption is strongly advised. Our present results also raise the possibility that rivaroxaban may be an acceptable alternative for patients who prefer the convenience of a DOAC; however, given the very small numbers reported here, further evaluation in this patient group is needed.

A 78-year-old man with relapsed, refractory IgG kappa plasma cell myeloma was commenced on daratumumab monotherapy in September 2019, having previously progressed through cyclophosphamide, bortezomib and dexamethasone (CyBorD); bortezomib, thalidomide and dexamethasone (VTD); and lastly, lenalidomide monotherapy. The latter was ceased after 7 months on the basis of both biochemical and radiological evidence of disease progression, with an 11 g/L increase in his IgG serum paraprotein and appearance of innumerable new lytic bone lesions. Daratumumab was commenced 3 days after cessation of lenalidomide at an initial dose of 16 mg/kg intravenously weekly. Upon commencement of therapy, a full blood count (FBC) demonstrated evidence of moderate marrow suppression, with a haemoglobin of 105 g/L, platelet count of 126×109/L and neutrophil count of 0.6×109/L. This was thought attributable to combination of plasma cell infiltration and myelosuppression from the recently ceased lenalidomide, although a bone marrow examination was not performed at this time. Within 2.5 months of the initiation of daratumumab, a marked deterioration in all three FBC lineages occurred, with the haemoglobin falling to 73 g/L, platelet count 95×109/L and neutrophil count 0.1×109/L. The patient received a total of three red cell transfusions on two separate occasions during this period. Cotrimoxazole antimicrobial prophylaxis was withheld. However the pancytopenia continued to progress, with a further FBC 2 weeks later demonstrating a haemoglobin of 65 g/L, platelet count of 53×109/L, and neutrophil count of 0.05×109/L. A reticulocyte count was inappropriately reduced at 15×109/L. Blood film examination revealed teardrop poikilocytosis and no circulating plasma cells. Bone marrow aspirate and trephine biopsy (Fig. 1) demonstrated profound hypocellularity with a predominance of erythroid precursors and virtual absence of granulopoiesis. No increase in blast cells was seen. Marrow plasma cells remained suppressed at <5% of total cellularity based on CD138 immunohistochemistry, which along with the reduction in IgG paraprotein to 1.9 g/L from a peak of 20 g/L, was consistent with daratumumab efficacy in inducing myeloma remission. Scattered small, monolobated megakaryocytes were encountered, however there was otherwise no evidence of granulocytic dysplasia. A diagnosis of marrow hypoplasia with agranulocytosis presumably induced by daratumumab was established. Daratumumab was accordingly ceased following the brief and ultimately unsuccessful employment of cyclosporin as empirical treatment for aplastic anaemia. Granulocyte colony stimulating factor (G-CSF) was also introduced at a dose of 300 μg subcutaneously thrice weekly. Nine weeks later, evidence of apparently spontaneous neutrophil count recovery was seen on a repeat FBC, however moderate anaemia and thrombocytopenia persisted. Despite this, the patient made an informed decision to pursue a palliative course of management and has since died. Daratumumab is an anti-CD38 monoclonal antibody approved by the United States Federal Drug Administration (FDA) as monotherapy for patients refractory to both a proteasome inhibitor and immunomodulatory therapy.1McKeage K. Daratumumab: first global approval.Drugs. 2016; 76: 275-281Crossref PubMed Scopus (66) Google Scholar Phase I and II trial data2Lonial S. Weiss B.M. Usmani S.Z. et al.Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial.Lancet. 2016; 387: 1551-1560Abstract Full Text Full Text PDF PubMed Scopus (517) Google Scholar,3Lokhorst H.M. Plesner T. Laubach J.P. et al.Targeting CD38 with daratumumab monotherapy in multiple myeloma.N Eng J Med. 2015; 373: 1207-1219Crossref PubMed Scopus (681) Google Scholar reported an incidence of therapy-associated cytopenias of 12–33%, with the incidence of neutropenia of grade 3 or higher severity ranging from 5% to 12%. Of patients in the phase II SIRIUS trial,2Lonial S. Weiss B.M. Usmani S.Z. et al.Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial.Lancet. 2016; 387: 1551-1560Abstract Full Text Full Text PDF PubMed Scopus (517) Google Scholar 38% received red cell transfusions and 8% required G-CSF. The mechanism responsible for daratumumab-induced myelosuppression is unclear, but the target CD38 is known to be present on myeloid stem cells where it acts to regulate neutrophil chemotaxis.4Partida-Sánchez S. Cockayne D.A. Monard S. et al.Cyclic ADP-ribose production by CD38 regulates intracellular calcium release, extracellular calcium influx and chemotaxis in neutrophils and is required for bacterial clearance in vivo.Nat Med. 2001; 7: 1209-1216Crossref PubMed Scopus (350) Google Scholar Severe neutropenia secondary to daratumumab monotherapy has previously been described in the post-marketing literature in a 73-year-old Japanese woman.5Nakamura F. Nasu R. Prolonged severe neutropenia after the first daratumumab administration for multiple myeloma with baseline neutropenia.Ann Hematol. 2019; 98: 2231-2232Crossref PubMed Scopus (2) Google Scholar Of note, both this patient and ours had a moderate neutropenia of 0.5–1.0×109/L at baseline, whereas the aforementioned clinical trials expressly excluded any participant with an initial neutrophil count of <1.0×109/L, a relatively common scenario in heavily pre-treated myeloma patients. Therefore, our case highlights the real-life risk of severe haematotoxicity associated with daratumumab when it is instigated in neutropenic patients outside the controlled setting of a clinical trial. However, both the Japanese case and ours send a similarly reassuring message with regard to the potential for reversibility of neutropenia. Complete neutrophil count recovery was observed within 2 months in both cases, following the cessation of daratumumab and administration of G-CSF therapy. Suggestion this phenomenon may be reversible provides an argument for at least the initial employment of appropriate supportive therapy in the event of neutropenia occurring whilst on daratumumab. Furthermore, it might be prudent to employ adjunctive routine G-CSF prophylaxis in those patients commencing daratumumab with neutrophil count <1.0×109/L who are also deemed at high risk of severe prolonged neutropenia.6Leleu X. Gay F. Flament A. Allcott K. Delforge M. Incidence of neutropenia and use of granulocyte colony-stimulating factors in multiple myeloma: is current clinical practice adequate?.Ann Hematol. 2018; 97: 387-400Crossref PubMed Scopus (9) Google Scholar Further investigation is required to better understand the natural history and identify potential risk factors for this rarely reported event ascribed to a novel therapy which for many Australasian patients remains their last resort. The authors state that there are no conflicts of interest to disclose.

BACKGROUND AND OBJECTIVES:It is recognized that blood transfusion services have an ethical duty to obtain informed consent from their voluntary, non-remunerated donors. This right was most recently affirmed by the 2017 revision of the International Society of Blood Transfusion (ISBT) Code of Ethics. However, the constituent elements necessary to adequately inform such consent have not been definitively established. MATERIALS AND METHODS:This review evaluates the historical background to informed consent in medicine and as it has been applied to blood donation. The question of what information should be disclosed is then considered with regard to existing statutory requirements in both the United States and EU as well guidance from relevant international organizations. The emerging ethical issues around repurposing of donated blood for sale as recovered plasma and use in research are included in this analysis. RESULTS:A reasonable basis is found in the literature to advocate that valid informed consent of blood donors should encompass: the donation process itself and potential adverse effects, the need for pre-donation transfusion-transmissible infection (TTI) screening, potential non-transfusion uses of derived products, requirements to obtain and store personal information, the consequences that non-disclosure of such information may have for both the donor and the recipient and reassurance as to the confidentiality of this information. CONCLUSION:Informed consent is a key component of the duty of care between a blood service and its donor. We identify essential elements that should be present for such consent to be considered valid.

Light chain deposition disease (LCDD) is a systemic disorder characterised by the pathologic deposition of immunoglobulin light chains, which is histologically distinguished from amyloidosis by failure to stain with Congo red. Central nervous system (CNS)-restricted LCDD is among the rarest manifestations. We describe a unique case complicated by focal onset epilepsy with impaired awareness for which control with anticonvulsant therapy proved difficult.

Objective Clozapine is the favoured antipsychotic for treatment-refractory schizophrenia, but has a 1%-2% incidence of agranulocytosis. Patients who require chemotherapy therefore pose a unique management dilemma for haematologists, oncologists and psychiatrists. Methods The Ovid MEDLINE and EMBASE databases were searched to identify reports describing use of clozapine concurrent with chemotherapy until 31 March 2019. The following terms (with variations) were used: neoplasm, cancer, tumour, malignancy, chemotherapy, antineoplastic and clozapine. Results Twenty-seven cases were included after reviewing titles and abstracts for relevance. Fifteen patients had solid organ tumours, and 12 had haematological malignancies, including three who underwent autologous haematopoietic stem cell transplantation (AutoHSCT). Clozapine was continued in 14 cases (albeit dose reduced in 2), with a reported median neutropaenic nadir of 0.29 x 10(9)/L (range 2.2 to <0.0 x 10(9)/L). Clozapine was discontinued or substituted for another antipsychotic in the remaining 13 cases, all except one of whom experienced marked psychiatric deterioration. The only neutropenia-related complication was one case of bacteraemia with high-dose melphalan conditioning for AutoHSCT. Conclusions These findings argue in favour of clozapine continuation during chemotherapy. Further research is needed to develop guidance to minimise the risk of neutropenia-related complications from concurrent treatment.

Bing-Neel syndrome (BNS) is characterised by infiltration of the central nervous system by lymphoplasmacytic lymphoma (LPL) cells and is traditionally regarded as a complication of pre-existing systemic Waldenstrom's macroglobulinaemia (WM). We describe the case of a 49 year old woman with leptomeningeal LPL who did not fulfil diagnostic criteria for concomitant systemic WM at presentation, and who failed to respond to conventional chemotherapy treatment (including high dose methotrexate) but did respond to the oral Bruton tyrosine kinase (BTK) inhibitor ibrutinib. This highlights an important variation in the typical natural history of this rare disease and also further supplements emerging evidence regarding efficacy of ibrutinib in its treatment. (C) 2019 Elsevier Ltd. All rights reserved.

AIMS:The purpose of this study was to identify predictors of remediation in a medical programme and assess the underlying causes and the quality of remediation provided within the context of a recent curriculum change.METHODS:A mixed methods study incorporating a retrospective cohort analysis of demographic predictors of remediation during 2013 and 2014, combined with thematic qualitative analysis of educator perspectives derived by interview on factors underlying remediation and the quality of that currently provided by the faculty.RESULTS:17.7% of all students required some form of remedial assistance and 93% of all students offered remediation passed their year of study. Multivariate analysis showed international students (OR 4.59 95% CI 2.62-7.98) and students admitted via the Māori and Pacific Admission Scheme (OR 3.43 2.29-5.15) were significantly more likely to require remediation. Male students were also slightly more likely than their female classmates to require assistance. No effect was observed for rural origin students, completion of a prior degree or completion of clinical placement in a peripheral hospital. Knowledge application and information synthesis were the most frequently identified underlying problems. Most faculty believed remediation was successful, however, flexibility in the programme structure, improved diagnostics and improved access to dedicated teaching staff were cited as areas for improvement.CONCLUSIONS:Remediation is required by nearly a fifth of University of Auckland medical students, with MAPAS and international students being particularly vulnerable groups. Remediation is largely successful, however, interventions addressing reasoning and knowledge application may improve its effectiveness.

BACKGROUND:Heart failure and its management represents a significant health burden, the extent of which is poorly understood in regional New Zealand.AIMS:To investigate mortality, quality of life, hospitalisation, and evidence-based medical and device management of severe left ventricular (LV) systolic dysfunction in a regional New Zealand setting.METHODS:A retrospective case series was undertaken of 1126 patients with a LV ejection fraction <36% on transthoracic echocardiograms performed between 1 October 1997 and 31 March 2011 in Nelson Marlborough District Health Board. All-cause mortality and hospitalisation data were analysed for all participants. Substudies were undertaken regarding pharmacotherapy, demographics, implantable cardioverter-defibrillator implantation rates and quality of life based on the EQ-5D questionnaire and New York Heart Association class.RESULTS:Five-year cumulative survival was 44.5%. The mean annual medical admission rate was 204/100 000; 54.84% of which were readmissions in the same year. Prescription rates for angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers, beta-blockers and spironolactone were 68.3%, 74.2% and 24.9%, respectively, with only 17.6%, 19.0% and 16.4% on maximum recommended doses. implantable cardioverter-defibrillator devices were inserted in 11.5% of eligible patients. Quality of life was impaired in patients <70 years relative to the age-approximated New Zealand index population. Mean EQ-5D visual analogue score was 72.6 ± 0.032 and self-reported New York Heart Association class 2.09 ± 0.107CONCLUSION:Patients with severe LV systolic dysfunction in this regional New Zealand community experience similar mortality and first hospitalisation rates to those seen elsewhere in patients with clinical heart failure, but a greater number of readmissions. Medical and device therapy utilisation was suboptimal, and quality of life impaired, together supporting the need for a dedicated heart failure service.

PURPOSE:To investigate the ability of optical coherence tomography (OCT) parameters of macular thickness (MT) and peripapillary retinal nerve fibre layer (RNFL) thickness to differentiate eyes with nonarteritic anterior ischaemic optic neuropathy (NAION) from uninvolved eyes and to identify the relationship between macular and RNFL parameters and visual field sensitivity (VFS).METHODS:Thirty patients with unilateral NAION participated in a prospective observational cross-sectional study. Patients underwent Humphrey visual field (SITA Standard 24-2, HVF) testing and OCT to measure MT and RNFL. The contralateral uninvolved eye was used as controls. Areas under the receiver operating characteristic curves (AUROCs) of MT and RNFL for discriminating NAION from control eyes were also determined. The prespecified outcome measure was the correlation between RNFL, MT and mean deviation (MD).RESULTS:Average RNFL and MT were thinner in NAION eyes: 72.8 μm versus 98.9 μm (p<0.0001) and 231.9 μm (SD, 21.4) vs. 251.1 μm (SD, 14.8; p=0.0001), respectively. The largest AUROCs were for average MT (0.87) and average RNFL thickness (0.88). Overall, macular parameters showed stronger correlation with VFS than RNFL parameters. The highest correlation was average MT (0.71; p<0.0001) followed by RNFL parameter nasal quadrant RNFL (0.40; p=0.030).CONCLUSION:Both MT and RNFL show strong correlations with level of VFS in NAION. Macular thickness showed more robust correlations with VF and provides strong surrogate marker of the level of damage in NAION.

Background: Congestive heart failure is associated with significant mortality, impaired quality of life and repeated hospital admissions. We sought to investigate this and examine the current evidence-based medical and device management of heart failure within Nelson-Marlborough. Methods: A retrospective longitudinal analysis of 1170 patients with left ventricular ejection fraction (LVEF) <36% was undertaken, based on transthoracic echocardiograms performed between December 1, 1997 and March 31, 2011. Five-year survival rates, acute admission numbers, medication use, access to implantable cardioverter-defibrillators (ICDs), quality of life based on the EQ-5D health questionnaire and self-reported New York Heart Association (NYHA) class were derived. Results: Mean LVEF was 25.54 ± 7.25%. Five-year cumulative survival was 36.9%. The mean annual admission rate was 210/100,000; 46.33% were re-admissions in the same year. Acute medical admission was associated with an increased risk of mortality (χ2 = 6.27, p < 0.02). Prescription rates for ACE inhibitors, beta-blockers and spironolactone were 68.3%, 74.2% and 24.9% respectively. Of these, only 17.6%, 19.0% and 16.4% were on maximum recommended doses. ICDs were inserted in 11.47% of patients aged ≤75 years as of 2006, who had also survived ≥18 months with LVEF persistently ≤30% for ≥3 months. Mean EQ-5D visual analogue score was 72.6 ± 0.032 and self-reported NYHA class 2.09 ± 0.11. Strong correlation was observed between NYHA class symptoms and overall quality of life (Pearson's r = −0.59). Conclusion: Current medical and device therapy amongst heart failure patients in Nelson and Marlborough is sub-optimal. Superior management to that observed here has been demonstrated through the implementation of dedicated heart failure services.

The adrenoleukodystrophies (ALDs) are a group of metabolic disorders characterised by the accumulation of very long-chain fatty acids in all tissues. The two most frequent ALD phenotypes are adult-onset adrenomyeloneuropathy (AMN) and childhood cerebral ALD. Visual system involvement in the adult phenotype is well described as impairment of visual function and optic disc pallor on clinical examination accompanied by demyelination of the optic nerves seen on MRI. Thinning of the retinal nerve fiber layer and ganglion cell death has been described in a neonatal form of ALD. Our patient provides evidence, through ocular coherence tomography scanning of the retina, that such degenerative changes also underlie the visual dysfunction seen in the AMN phenotype.