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Background There is an absence of clinically relevant epidemiological data in regional Australia pertaining to haematological malignancies. Aim To determine the incidence and geographical variation of haematological malignancies in North Queensland using a clinically appropriate disease classification. Methods Retrospective, observational study of individual patient data records of all adults diagnosed with a haematological malignancy between 2005-2014 and residing within The Townsville Hospital Haematology catchment region. We report descriptive summaries, incidence rates and incidence-rate ratios of haematologic malignancies by geographic regions. Results 1581 haematological malignancies (69% lymphoid, 31% myeloid) were diagnosed over the 10-year study period. Descriptive data is presented for 58 major subtypes as per the WHO diagnostic classification of tumours of haematopoietic and lymphoid tissues. The overall median age at diagnosis was 66 years with a male predominance (60%). We demonstrate a temporal increase in the incidence of haematologic malignancies over the study period. We observed geographical variations in the age-standardised incidence rates per 100,000 ranging from 0.5 to 233.5. Our data suggests an increased incidence rate ratio for haematological malignancies in some postcodes within the Mackay area compared to other regions. Conclusion This study successfully reports on the incidence of haematological malignancies in regional Queensland using a clinically meaningful diagnostic classification system and identifies potential geographic hotspots. We advocate for such contemporary, comprehensive, and clinically meaningful epidemiological data reporting of blood cancer diagnoses in wider Australia. Such an approach will have significant implications toward developing appropriate data-driven management strategies and public health responses for haematological malignancies. This article is protected by copyright. All rights reserved.

Background: Acute limb ischaemia (ALI) is a limb and life-threatening condition with significant morbidity. There are currently no consensus recommendations for the investigative practices to determine the aetiology of ALI presenting without a known aetiology. We undertook a detailed analysis of all investigations performed to identify an underlying precipitant in those with unexplained ALI and formulated a suggested diagnostic algorithm for the evaluation of unexplained ALI. Methods: ALI cases presenting to a tertiary referral centre over a 3-year period were reviewed, and known aetiologies, and investigations undertaken to determine the underlying aetiology of unexplained ALI were obtained. Results: Unexplained ALI was found in 27 of 222 patients (12%), of which 21 (78%) had a cause for ALI established after further investigations. Six patients had no cause identified despite extensive work-up. Most patients with unexplained ALI had a cardioembolic source identified as the underlying cause (62%), and this included atrial fibrillation, infective endocarditis, cardiac myxoma and intra-cardiac thrombus. Other causes of unexplained ALI were detected by computed tomography (CT) imaging and included newly diagnosed significant atherosclerotic disease (19%), embolism from isolated proximal large vessel thrombus (10%) and metastatic malignancy (10%). There were no cases attributed to inherited thrombophilias, myeloproliferative neoplasms or anti-phospholipid syndrome. Conclusion: Among patients with unexplained ALI, the majority had a cardioembolic source highlighting the importance of comprehensive cardiac investigations. A subset of patients had alternative causes identified on CT imaging. These data support the use of a collaborative and integrative diagnostic algorithm in the evaluation of unexplained ALI.

A retrospective, observational study was performed of 112 patients who underwent autologous haematopoietic stem cell transplantation (ASCT) to determine the relationship between CD34+ stem cell dose and neutrophil engraftment. Importantly, a novel approach to more accurately calculate time to neutrophil engraftment was employed. The results demonstrated that a higher CD34+ stem cell dose was associated with faster neutrophil recovery (P

Neoantigens are generated by mutations acquired in malignant cells. To be immunogenic, neoantigen peptides must be processed and then presented by HLA molecules on the tumor cell surface to evoke a T cell response. Emerging evidence suggests neoantigens are promising new targets of personalised cancer immunotherapies, provided that antigen presentation remains intact. Recently, we (Tobin, JCO 2019) demonstrated the link between the tumor microenvironment (TME) and clinical outcome in patients with advanced-stage Follicular Lymphoma (ASFL). In particular, ASFL patients with favorable outcomes had high levels of immune infiltration (best stratified by PD-L2 expression) with increased intratumoral CD8+ T cell clonotypes suggestive of expanded antigen-specific T cells in response to presentation by HLA class I neoantigens. This is supported by HLA class I pathway genetic aberrations being infrequent (unlike HLA class II) in FL. However, to date there is minimal data on the frequency and nature of putative neoantigens, their relationship with HLA class I antigen presentation and with the TME in any stage of FL. In particular, the immunobiology of early-stage FL (ESFL) has been largely neglected. Here, we present detailed characterization of these parameters in patients with early-stage FL (ESFL) from the TROG99.03 prospective clinical trial (MacManus, JCO 2018). Digital multiplex gene expression (770 gene PanCancer Immune Panel, NanoString) and targeted NGS (365 genes recurrently mutated in hematological malignancies) was performed on 97 FFPE diagnostic tissue samples. Intratumoral CD8A expression cut-off derived by maximally selected rank statistics was associated with >2-fold differential median PFS (CD8Ahi: 11.5 years vs. CD8Alo: 4.9 years, p=0.0042, Figure 1A). In keeping with a relationship between HLA class I immune effector infiltration within the TME and FL tumor antigen presentation/processing, expression of NLRC5 (a transcriptional activator of HLA class I) was also associated with differential median PFS (NLRC5hi: 10.8 years vs. NLRC5lo: 4.9 years, p=0.021, Figure 1B). The impact of expression of CD8A and NLRC5 were independent of mutations in BCL-2,TP53 and all but of one the m7-FLIPI genes. The exception was EZH2, mutations of which were enriched in cases with reduced CD8A (p=0.0066) and NLRC5 (p Next, we investigated the expression of HLA class I and predicted neoantigens. HLA genotyping was performed using a custom sequencing panel on matched germline peripheral blood DNA for 71 TROG99.03 diagnostic samples. For the corresponding somatic coding variants, the strongest HLA class I binding efficiencies were calculated using 8 epitope prediction algorithms. 41% of samples had no detectable neoantigens, whereas 59% of samples had ≥1 neoantigens detected, with 116 neoantigens total. Importantly, unsupervised hierarchical clustering showed 2-fold enrichment of samples with neoantigens among those with elevated HLA A/B expression vs. samples with low HLA A/B (p=0.0023, Figure 1C). Interestingly, roughly one third of neoantigens were due to indels causing frameshift events resulting in the generation of 'non-self' peptides with strong predicted binding affinity. Recently TCGA data has been used to show that frameshift variants occurring at different sites in a gene can converge to generate a handful neo open reading frame peptides ('NOPs') common to multiple cancer patients. Therefore, it has been postulated that these NOPs could have a considerable therapeutic potential as a novel pan-cancer 'semi-personalized' immunotherapy. In keeping with data derived in solid tumors, in ESFL we observed frameshift variants were most frequently observed in KMT2D. Finally, 5 relapsed/transformed FL samples were compared to their paired diagnostic tissue samples. Not only did neoantigens present at diagnosis typically remain detectable, but in several cases additional neoantigens were also found. In summary, we demonstrate for the first time in ESFL that neoantigens are typically associated with intact HLA class I presentation; CD8 infiltration within the TME is related to tumor antigen processing and associated with favorable outcomes; and that a subset of FL tumors have NOPs. These data have important implications for the design of innovative next-generation immunotherapies in FL. Disclosures Keane: BMS: Research Funding; Celgene: Honoraria, Other: Travel; Roche: Honoraria, Other: Travel, Speakers Bureau; MSD Oncology: Honoraria, Other: Travel; Gilead: Honoraria, Other: Travel, Speakers Bureau. Blombery:Amgen: Consultancy; Novartis: Consultancy; Janssen: Honoraria; Invivoscribe: Honoraria. Tobin:Gilead: Research Funding. Seymour:Nurix: Honoraria; Morphosys: Consultancy, Honoraria; Mei Pharma: Consultancy, Honoraria; Gilead: Consultancy; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Gandhi:Celgene: Research Funding; Bristol-Myers Squibb: Research Funding; Merck Sharp & Dohme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Gilead Sciences: Honoraria; Genentech: Honoraria; Mater Research: Current Employment; Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Other: Travel, accommodation, expenses .

The aim of this descriptive study was to assess the prevalence of vitamin D deficiency in patients on active therapy for multiple myeloma in a tropical climate. We also tested for the association of vitamin D status on clinical outcomes. This was a single centre, observational study performed in Townsville, Australia, which has a sunlight heavy, tropical climate. Patients on active therapy for multiple myeloma underwent testing of serum 25-hydroxyvitamin D (25(OH)D). Information on disease stage, skeletal morbidity and symptoms of peripheral neuropathy were collected from medical records and self-reported patient questionnaires. A total of 41 patients were included. With a median disease duration of 38 months, 27% were found to be vitamin D deficient. Patients with vitamin D deficiency had a higher likelihood of peripheral neuropathy compared with their non-vitamin D counterparts (73% vs. 33%, P = 0.03). Although those with vitamin D deficiency had more skeletal morbidity, this was not statistically significant (73% vs 50%, P = 0.19). Reduced 25(OH) D was associated with a poor performance status (P = 0.003). There was no association between vitamin D status and stage of myeloma. There is a relatively high prevalence of vitamin D deficiency in patients with myeloma in our study. This is despite a sunlight heavy, tropical climate. We report an association between vitamin D deficiency and peripheral neuropathy. Prospective interventional trials are required to further assess this.

To the Editor: We welcome the contribution of Bahrainwala et al1 in highlighting the perioperative care of patients receiving long-term dialysis. Consistent with previous studies, the authors quote a 10-fold higher relative risk for in-hospital mortality for patients receiving maintenance dialysis undergoing elective surgery compared with those without chronic kidney disease (CKD).2 However, we believe that using relative risk estimates with patients without CKD as a benchmark for comparison provides an inflated perception of perioperative mortality. Rather, shared decision making between dialysis patients and clinicians should consider individual survival trajectories to provide context to perioperative risk assessment. Relative risk is often benchmarked against a healthy non-CKD comparator group and can often provide elevated and misleading risk stratification. Measures of relative risks with patients without CKD may not be the appropriate comparator. Comparisons should be made with patients receiving longterm dialysis matched for age and comorbid conditions who are not undergoing surgery for the same surgical condition. Judicious interpretation of these estimates is important in individualizing and tailoring prognostic information. Moreover, although outcome data are largely based on mortality events, patients receiving long-term dialysis are at greater risk for postsurgical morbidity, including loss of physical function and independence. Perioperative risk metrics often neglect these key patientimportant outcome measures.3,4 We advocate a holistic and measured approach to estimating perioperative risk in this population with an emphasis on individualizing assessment for patients.

Background: The Townsville Hospital is a tertiary hospital in North Queensland with one of the largest regional transplant centres in Australia, performing primarily autologous haemopoietic stem cell transplants (HSCT) for various haematological malignancies. Aims: This single-centre, retrospective, observational study aims to describe the activity and outcomes of autologous HSCT at The Townsville Hospital between 2003 and 2017 to verify safety standards. Methods: Patient-level data were collected, including demographics, frequency and indication for transplant, conditioning, current clinical status and cause of death. Key outcomes included overall survival, non-relapse mortality, incidence of therapy-related neoplasm and causes of death. Progression-free survival in the multiple myeloma (MM) subgroup was also assessed. Results: There were 319 autologous HSCT in 286 patients, with a median age of 58 years (range 14-71 years); 62% of patients were male. Indications for transplantation were: MM 53.7%, non-Hodgkin lymphoma 29.4%, Hodgkin lymphoma 5.0% and other 11.9%. Causes of death were: disease progression/relapse (65.2%), second malignancy (17.0%), infection (9.8%) and other (8.0%). Non-relapse mortality was 1.2% (95% confidence interval 0.4-3.0) and 3.2% (1.7-5.7) at 100 days and 1 year, respectively, post-HSCT. Overall survival at 2 years was 81.0% (73.8-86.4) for MM and 69.6% (58.8-78.1) for non-Hodgkin lymphoma. The median progression-free survival in the MM cohort was 3.3 years. Conclusion: The Townsville Hospital transplant centre provides an important transplant service in regional Queensland, with outcomes comparable to national data. We reported a relatively high rate of second malignancy as a cause of death.

Catastrophic antiphospholipid syndrome is a rare condition with high morbidity and mortality. We present a refractory case of catastrophic antiphospholipid syndrome with a view to highlight the importance of early identification and aggressive treatment of this condition. A 36-year-old female presented with clinical manifestations of multiorgan vascular occlusion with a known history of primary antiphospholipid syndrome. The presentation was on a background of a recent change of her long-term anticoagulation from warfarin to therapeutic low-molecular-weight heparin. Given that multiorgan involvement with 3 organ systems occurred nearly simultaneously, a diagnosis of probable catastrophic antiphospholipid syndrome was made. Prompt therapeutic anticoagulation, antiplatelet, and glucocorticoid therapy was commenced. Despite this, the patient continued to demonstrate clinical features concerning for ongoing small vessel occlusion necessitating aggressive immunomodulatory therapy in the form of intravenous immunoglobulin, plasma exchange, and rituximab.

With much interest, we have read the paper by Szerlip et al. [(1)][1] on adverse outcomes after transcatheter aortic valve replacement (TAVR) in patients with end-stage renal disease (ESRD). Studies have consistently demonstrated that patients with ESRD on chronic dialysis are at increased risk for

Aim There is a paucity of data pertaining to the incidence of biopsy-proven glomerulonephritis (GN) in Australia. This retrospective study aims to review the data from all adult native renal biopsies performed in the state of Queensland from 2002 to 2011 – comparing results with centres from across the world. Methods Pathology reports of 3697 adult native kidney biopsies were reviewed, of which 2048 had GN diagnoses. Age, gender, clinical indication and histopathology findings were compared. Results The average age at biopsy was 48 ± 17 years. Male preponderance was noted overall (∼60%), with lupus nephritis being the only individual GN with female predilection. The average rate of biopsy was 12.04 per hundred thousand people per year (php/yr). Nephrotic and nephritic syndromes comprised approximately 75% of all clinical indications that lead to GN diagnoses. IgA nephropathy (1.41 php/yr) was the most common primary GN followed by focal segmental glomerulosclerosis (1.02 php/yr) and crescentic GN (0.73 php/yr). Diabetic nephropathy (0.84 php/yr), lupus nephritis (0.69 php/yr) and amyloidosis (0.19 php/yr) were the most commonly identified secondary GN. Conclusion IgA nephropathy is the predominant primary GN in Queensland, and nephrotic syndrome the most common indication for a renal biopsy. While crescentic GN incidence has significantly increased with time, focal segmental glomerulosclerosis incidence has not shown any trend. Incidence of GN overall appears to increase with age. The annual rate of biopsy in this study appears lower than previously published in an Australian population.

Background: The CHA2DS2-VASc score is the standard of care in thromboembolic risk assessment for patients with non-valvular atrial fibrillation (AF). Most patients will undergo transthoracic echocardiography (TTE) for further evaluation, and many also having transesophageal echocardiography (TEE) performed prior to cardioversion or ablation. We sought to evaluate the relationship between left atrial (LA) abnormalities detected on TEE and TTE parameters, to determine if imaging may be additive in risk assessment.Methods: Clinical, TEE and TTE data for patients in AF at the time of their study were included in this retrospective analysis. LA/LA appendage (LAA) abnormalities on TEE included the presence of spontaneous echo contrast, sludge, thrombus and LAA emptying velocity 90% in both groups. Median LAVI, septal e’ and E wave velocity in the ≤ 1 vs ≥2 groups were 46ml/m2vs 48ml/m2, 8cm/s vs 6cm/s and 0.8m/s vs 0.8m/s, respectively. Overall, increased LAVI and reduced septal e’ on TTE was associated with TEE LA/LAA abnormalities (p=0.02, p=0.005 respectively). In subgroup analysis, it was found that LAVI and septal e’ was statistically significant in the low CHA2DS2-VASc group (p=0.03, p =0.01), but not in the higher CHA2DS2-VASc group (p=0.21, p=0.30).Conclusion: TEE LA/LAA abnormalities were not infrequently noted in those patients traditionally deemed low risk (CHA2DS2-VASc ≤ 1). LAVI and septal e’ on TTE appear to be associated with LA/LAA abnormalities detected on TEE, which was particularly relevant in lower CHA2DS2-VASc patients and may be additive to conventional clinical risk assessment. Further study is needed to evaluate the role of imaging in AF thromboembolic risk stratification, and whether this translates to prognostic and clinical endpoints.