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Vitamin D insufficiency is a potentially modifiable risk factor for poor outcomes in newly diagnosed large B-cell lymphoma (LBCL). However, the role of circulating vitamin D concentrations in relapsed/refractory LBCL treated with CD19-directed chimeric antigen receptor T-cell therapy (CAR-T) is currently unknown. This was a single-center, observational study that evaluated the association of pre-CAR-T 25-hydroxyvitamin D (25-OHD) status with 100-day complete response, progression-free survival, overall survival, and CAR-T-related toxicity in 111 adult relapsed/refractory LBCL patients. Vitamin D insufficiency was defined as ≤30 ng/mL in accordance with the Endocrine Society guidelines. The median pre-CAR-T 25-hydroxyvitamin D concentration was 24 ng/mL (interquarile range = 18-34). Vitamin D-insufficient patients (≤30 ng/mL; n = 73 [66%]) were significantly younger than their vitamin D-replete (30 ng/mL; n = 38 [34%]) counterparts (P= .039). The vitamin D-insufficient cohort was enriched for de novo LBCL as the histological subtype (P= .026) and had a higher proportion of tisagenlecleucel as the CAR-T product (P= .049). There were no other significant differences in the baseline characteristics between the two groups. In vitamin D-insufficient compared to -replete patients, 100-day complete response was 55% versus 76% (P= .029), and 2-year overall survival was 41% versus 71% (P= .061), respectively. In multivariate analysis, vitamin D insufficiency remained significantly associated with 100-day complete response (odds ratio 2.58 [1.05-6.83]; P= .045) and overall survival (hazard ratio 2.24 [1.08-4.66], P= .030). In recipients of tisagenlecleucel, vitamin D insufficiency was associated with significantly lower cell viability of the infused CAR-T product (P= .015). Finally, pretreatment vitamin D insufficiency did not predict for subsequent CAR-T-related toxicity. This is the first report to demonstrate that vitamin D insufficiency is associated with inferior clinical outcomes in CAR-T recipients. Further study into the mechanistic insights of this finding, and the potential role of vitamin D supplementation to optimize CAR-T are warranted.

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.

Data on the prognostic impact of pretherapy 18F-fluorodeoxyglucose–positron emission tomography (FDG-PET) in follicular lymphoma (FL) is conflicting. The predictive utility of pretherapy total metabolic tumor volume (TMTV) and maximum standardized uptake value (SUVmax) on outcome appears to vary between regimens. Chemoimmunotherapies vary in the extent of T-cell depletion they induce. The role of intratumoral T cells on pretherapy FDG-PET parameters is undefined. We assessed pretherapy FDG-PET parameters and quantified intratumoral T cells by multiple methodologies. Low intratumoral T cells associated with approximately sixfold higher TMTV, and FL nodes from patients with high TMTV showed increased malignant B-cell infiltration and fewer clonally expanded intratumoral CD8+ and CD4+ T-follicular helper cells than those with low TMTV. However, fluorescently labeled glucose uptake was higher in CD4+ and CD8+ T cells than intratumoral B cells. In patients with FDG-PET performed prior to excisional biopsy, SUVmax within the subsequently excised node associated with T cells but not B cells. In summary, TMTV best reflects the malignant B-cell burden in FL, whereas intratumoral T cells influence SUVmax. This may contribute to the contradictory results between the prognostic role of different FDG-PET parameters, particularly between short- and long-term T-cell–depleting chemoimmunotherapeutic regimens. The impact of glucose uptake in intratumoral T cells should be considered when interpreting pretherapy FDG-PET in FL.

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

Over the past decade therapies targeting the PD-1 axis with monoclonal antibodies to reinstate host immune function have revolutionized the clinical management of some cancers but have had minimal impact on others. This dichotomy is exemplified by B cell lymphomas. Whilst striking results are observed in classical Hodgkin Lymphoma (cHL) and Primary Mediastinal B Cell Lymphoma (PMBL), responses in other B cell lymphomas are infrequent. Even with cHL and PMBL, responses are not always durable and adverse effects can result in treatment discontinuation. A more nuanced approach to manipulate the PD-1 axis is required before the full benefits of PD-1 axis blockade can be realised. In this review, we provide an outline of PD-1 axis biology, including the range of cellular expression, the molecular mechanisms underlying regulation and the impacts of downstream signalling. These may permit the development of alternate strategies to PD-1 axis blockade to enhance the therapeutic efficacy in B cell lymphomas.

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.

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.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.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.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.

Karthik D Nath,1,2 Julie G Burel,1 Viswanathan Shankar,3 Antonia L Pritchard,1 Michelle Towers,2 David Looke,1,2 Janet M Davies,1 John W Upham1,2 1The University of Queensland (School of Medicine), Brisbane, QLD, Australia; 2Princess Alexandra Hospital, Brisbane, QLD, Australia; 3Department of Epidemiology and Population Health, Albert Einstein College of Medicine, New York, NY, USA Background and objective: Individuals with chronic obstructive pulmonary disease (COPD) are at a high risk of developing significant complications from infection with the influenza virus. It is therefore vital to ensure that prophylaxis with the influenza vaccine is effective in COPD. The aim of this study was to assess the immunogenicity of the 2010 trivalent influenza vaccine in persons with COPD compared to healthy subjects without lung disease, and to examine clinical factors associated with the serological response to the vaccine. Methods: In this observational study, 34 subjects (20 COPD, 14 healthy) received the 2010 influenza vaccine. Antibody titers at baseline and 28 days post-vaccination were measured using the hemagglutination inhibition assay (HAI) assay. Primary endpoints included seroconversion (≥4-fold increase in antibody titers from baseline) and the fold increase in antibody titer after vaccination. Results: Persons with COPD mounted a significantly lower humoral immune response to the influenza vaccine compared to healthy participants. Seroconversion occurred in 90% of healthy participants, but only in 43% of COPD patients (P=0.036). Increasing age and previous influenza vaccination were associated with lower antibody responses. Antibody titers did not vary significantly with cigarette smoking, presence of other comorbid diseases, or COPD severity. Conclusion: The humoral immune response to the 2010 influenza vaccine was lower in persons with COPD compared to non-COPD controls. The antibody response also declined with increasing age and in those with a history of prior vaccination. Keywords: COPD, human influenza, humoral immunity, influenza vaccines, vaccination