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Population-based studies have demonstrated a high risk of second cancers, especially of the skin, among patients with chronic lymphocytic leukaemia (CLL). We describe age-standardised incidence ratios (SIRs) of second primary malignancies (SPM) in Australian patients with relapsed/refractory CLL treated with at least two lines of therapy, including ibrutinib. From December 2014 to November 2017, 156 patients were identified from 13 sites enrolled in the Australasian Lymphoma and Related Diseases Registry, and 111 had follow-up data on rates of SPM. At 38.4 months from ibrutinib therapy commencement, 25% experienced any SPM. SIR for melanoma and all cancers (excluding nonmelanomatous skin cancers) were 15.8 (95% confidence interval (CI): 7.0-35.3) and 4.6 (95% CI: 3.1-6.9) respectively. These data highlight the importance of primary preventive interventions and surveillance, particularly as survival from CLL continues to improve.

The difference in the mixing timescale among species, i.e., differential mixing, is a combined result due to the difference in molecular diffusivity and the difference in reaction-induced scalar gradient. Being a key component for micro-mixing, incorporating differential mixing is a desirable feature for a transported probability density function (TPDF) simulation. Nevertheless, the lack of understanding of differential mixing hinders its model development. This paper intends to address that whether there exist critical species for differential mixing, such that considering only the differential mixing of these species can reproduce the prediction with the full differential mixing of all species. To achieve so, TPDF simulations have been performed for a temporally evolving, non-premixed ethylene DNS flame, with the DNS-extracted mean velocity, turbulent diffusivity and species mixing timescales to enable a clean assessment on the critical species for differential mixing. An algorithm based on active subspace (AS) method is proposed to identify the critical species. It is found that the identified 10 critical species are neither the ones having the highest mixing frequency nor the ones causing the largest temperature change. The TPDF simulation with the differential mixing of the 10 critical species can well reproduce the mean and conditional mean quantities of the reference simulation with the full differential mixing of all species, illustrating the effectiveness of the AS method. Compared to the crude single-species trial method, the AS method better identifies the critical species as it accounts for the coupling nature of the chemical reaction system. By analyzing the reaction pathway in 1D opposed jet flames, it is found that the critical species all involve in the controlling reactions for the overall combustion process, thus providing a physical interpretation for the identified critical species. The effects of quantity of interest and micro-mixing model on cr

PURPOSE: Cancer-related cognitive impairment (CRCI) is a recognised adverse consequence of cancer and its treatment. This qualitative sub-study was undertaken as part of a larger prospective longitudinal study in which recruitment and retention were very high. The aim was to gain an understanding of participants reasons for ongoing participation, at a time of heightened stress related to a new diagnosis of aggressive lymphoma and the rapid commencement of treatment. METHODS: This qualitative descriptive sub-study included semi-structured interviews with twenty-seven participants. Interviews were recorded and transcribed, and a thematic descriptive approach was used to analyse the data. RESULTS: Twenty-seven interviews were completed. Four themes described participants' motivation to consent and continue with the study. These included ease of participation, personal values, self-help and valued additional support. Participants understood the requirements of the study, and data collection occurring during hospital visits was perceived to be convenient. Interviewees confirmed that the study fulfilled desire to "help others". Although testing was intense and challenging, it provided feedback on current functioning and was described by some as a "welcome distraction" and enjoyable. Finally, interaction with the study nurse was perceived as an additional beneficial oversight and support. CONCLUSION: Achieving sustained participation in a prospective study with patients undergoing treatment is facilitated where the logistical demands of data collection are minimised; a clinician from the service is included; the tasks are seen as inherently interesting; and care is taken to provide empathic support throughout. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12619001649101.

PURPOSE: Treatment strategies of lymphoid malignancies have been revolutionized by immunotherapy. Because of the inherent property of Hodgkin lymphoma and some subtypes of non-Hodgkin lymphoma as a highly FDG-avid tumor, functional 18F-FDG PET/CT imaging is already embedded in their routine care. Nevertheless, the question is whether it is still valuable in the context of these tumors being treated with immunotherapy. Herein, we will review the value of 18F-FDG PET/CT imaging lymphoid tumors treated with immunotherapy regimens. METHODS: A comprehensive literature search of the PubMed database was conducted on the value of the 18F-FDG PET/CT for immunotherapy response monitoring of patients with malignant lymphoma. The articles were considered eligible if they met all of the following inclusion criteria: (a) clinical studies on patients with different types of malignant lymphoma, (b) treatment with anti-CD20 antibodies, immune checkpoint inhibitors or immune cell therapies, (c) and incorporated PET/CT with 18F-FDG as the PET tracer. RESULTS: From the initial 1488 papers identified, 91 were ultimately included in our study. In anti-CD20 therapy, the highest pooled hazard ratios (HRs) of baseline, early, and late response monitoring parameters for progression-free survival (PFS) belong to metabolic tumor volume (MTV) (3.19 (95%CI: 2.36-4.30)), maximum standardized uptake value (SUVmax) (3.25 (95%CI: 2.08-5.08)), and Deauville score (DS) (3.73 (95%CI: 2.50-5.56)), respectively. These measurements for overall survival (OS) were MTV (4.39 (95%CI: 2.71-7.08)), DS (3.23 (95%CI: 1.87-5.58)), and DS (3.64 (95%CI: 1.40-9.43)), respectively. Early and late 18F-FDG PET/CT response assessment in immune checkpoint inhibitors (ICI) and immune cell therapy might be an effective tool for prediction of clinical outcome. CONCLUSION: For anti-CD20 therapy of lymphoma, the MTV as a baseline 18F-FDG PET/CT-derived parameter has the highest HRs for PFS and OS. The DS as visual criteria in

A hydrogen-diesel dual direct injection (H2DDI) combustion strategy in a compression-ignition engine is investigated numerically, reproducing the configuration of previous experimental investigations. These experiments demonstrated the potential of up to 50% diesel substitution by hydrogen while maintaining high engine efficiency; nevertheless, the emission of NOx increased compared with diesel operation and was strongly dependent on the hydrogen injection timing. This implies the efficiency and NOx emission are closely associated with hydrogen charge stratification; however, the underlying mechanisms are not fully understood. Aiming to highlight the hydrogen injection-timing influence on hydrogen/air mixture stratification and engine performance, the present study numerically investigates the mixture formation and combustion process in the H2DDI engine concept using Converge, a three-dimensional fluid dynamics simulation code. Increased hydrogen stratification levels are realised by retarding the hydrogen injection timing from 180 °CA to 40 °CA bTDC at fixed energy substitution ratio of 50%, as in the experiments. The simulations are validated against the measured pressure and apparent heat release rate traces. The simulation results show that early hydrogen injection yields an almost homogeneous mixture with entire hydrogen charge being in fuel-lean conditions, leading to a primarily premixed combustion process of the hydrogen fuel. The intermediate injection timings produce a moderately stratified hydrogen mixture with much of the hydrogen at near-stoichiometric conditions, which achieves the highest engine efficiency but also the highest NOx emissions. The late injection forms a highly stratified charge with most hydrogen mixtures in fuel-rich conditions, presenting a mixing-controlled combustion process. This combustion mode induces the lowest wall heat loss and the lowest NOx emissions, but yields a relatively high fraction of unburnt hydrogen and efficiency p

The combustion process of a homogeneous hydrogen charge in a small-bore compression ignition engine with diesel-pilot ignition was simulated using the CONVERGE computational fluid dynamics code. Analysis of the simulation results aimed to understand the processes leading to NOx production and heat loss in this combustion strategy, and their dependence on the hydrogen fuel energy fraction. Previous experimental results demonstrated promising performance, but this comes with a penalty in increased NOx emissions and potentially higher heat losses. The present study aims to enhance understanding of the mechanisms governing these phenomena. The simulated engine was initialised with a lean homogeneous hydrogen-air mixture at BDC and n-dodecane was injected as a diesel surrogate fuel near TDC. The simulations were validated based on experimental results for up to 50% hydrogen energy fraction, followed by an exploratory study with variation of the energy fraction from 0% to 90%. The addition of hydrogen increased the ignition delay and changed the combustion mode from typical diesel combustion to a premixed burn involving flame propagation. The causes of NOx emissions and heat loss trends in the simulations are investigated through an analysis of the temperature and equivalence ratio distributions in the engine. The results show that NOx production peaks at approximately 50% hydrogen, before decreasing as combustion becomes more premixed, which is shown to result in lower peak temperature. Heat loss is significant at all hydrogen energy fractions, but highest at intermediate values. Differences in the wall heat transfer are driven by the near-wall equivalence ratio, turbulence, and combustion phasing.

Background: Most DLBCL & FL responds well to first line treatment, yet relapsed disease outcomes are poor. Immune checkpoint inhibition (ICI) with PD/PD1 inhibitors (PD1i) yield high response rates in some lymphomas; though single agent PD1i yields a disappointing ORR of 10% in heavily pre-treated DLBCL, some responses are durable. RT stimulates anti-tumour immunity through several mechanisms and may enhance response to ICI. Concurrent ICI & RT is synergistic in preclinical studies & solid tumours, improving local & distant (abscopal) response. RT to multiple disease sites may broaden the spectrum of tumour antigen release and overcome clonal variation between disease sites to further augment the immune response. A dose-response relationship between RT and antigen release has yet to be established. This phase I dose escalation study aims to determine the safety profile of RT in combination with durvalumab, an anti-PD-L1 monoclonal antibody, in relapsed/refractory DLBCL and FL. Study Design and Methods: RaDD (NCT03610061) is a phase I dose escalation study to determine the safety profile of escalating dose and number of sites of RT in combination with durvalumab in relapsed/refractory (RR) DLBCL & FL. Eligible patients (pts) have received >= 1 prior line of therapy and are ineligible for or relapsed after autologous stem cell transplant (auto-SCT). Pts with active autoimmune disease, CNS involvement, prior allogeneic-SCT or chronic steroid use are excluded. RT dose and site escalation proceeds according to a 3+3 design with 6 dose levels (cohorts 1-6). Treatment comprises external beam RT to target site(s) daily for 5 days (Cohorts 1-5); Cohort 6 receives a further 5 daily fractions (max 30Gy). Durvalumab 1500mg IV commences day 2 of RT and continues 4-weekly until disease progression. Pts can continue until a second radiological progression if clinical benefit is ongoing. The dose limiting toxicity period is 28 days from start of RT. The primary endpoint is the toxi

Aim: Primary Central Nervous System Lymphoma (PCNSL) [i.e. diffuse large B-cell lymphoma of the CNS] is a rare and poor-prognosis disease occurring predominantly in older patients (median age >60 years old). Prospective studies of two commonly used chemoimmunotherapy (CIT) protocols, MATRix and MPV/Ara-C (+/- rituximab), have reported 2-year PFS and OS of 57-61% and 69-81% respectively. Our aim was to evaluate registry-reported outcomes of frontline CIT strategies employed at Australasian sites. Method(s): A retrospective study of consecutive, immunocompetent, adult PCNSL patients (WHO criteria: 2017) treated with curative-intent CIT, from 10 sites (9 Australian, 1 Singaporean) between 1 st January 2009 and 31 st December 2018 (i.e. ten-year period). Overall survival (OS) and progression-free survival (PFS) were calculated using the Kaplan-Meier (log-rank) method. Univariate associations were derived using a Cox model with variables p<0.10 entered stepwise into a multivariate model. Result(s): Data was collected on 207 patients, 189 of whom met WHO diagnostic criteria for PCNSL (i.e. diffuse large B-cell lymphoma of the CNS). We excluded patients with insufficient data (6), non-DLBCL histology (6), secondary PCNSL (3) and post-transplant lymphoproliferative disorder (3). Of these, 176 (93%) received curative-intent CIT. The majority (66%) were over 65 years of age (median: 65, range: 25-87); ECOG performance status was >= 2 in 31% (data not available for 14% of patients). The majority were male (55%) and had deep structure involvement (64%). International Extranodal Lymphoma Study Group (IELSG) risk criteria could not be calculated in many patients due to missing data (predominantly LDH and CSF protein). CSF involvement was rare (n=23, 13%) but data was only available for 60% of patients. Of the 159 with documented renal function, 26% had renal impairment (defined as Cockroft-Gault creatinine clearance <60ml/min or eGFR <90ml/min). Five CIT regimens were used: MATRi

Background: MCL is a rare and incurable disease representing 5-10% of all non-Hodgkin lymphoma cases. Although intensive chemotherapy induction and up-front ASCT can induce durable remissions in fit patients, toxicity can be significant. R-DHAOx chemoimmunotherapy provides adequate outcomes and a favourable toxicity profile compared to some other induction regimens (Le Gouill S Blood 2017). The highly selective Bruton tyrosine kinase inhibitor (BTKi) acalabrutinib has minimal off-target activity and proven efficacy in relapsed MCL (Wang M Lancet 2018), however, direct combination of BTKi & chemoimmunotherapy is toxic. Thus, it is postulated that up-front use with an acalabrutinib 'window' before chemoimmunotherapy, followed by maintenance after intensive chemotherapy will prolong time to next treatment and reduce overall treatment toxicity (Kuruvilla J Hematol Oncol 2017). Method(s): The WAMM study is an ALLG-sponsored investigator-initiated multicentre single-arm phase 2 trial (ACTRN1269000990123). Eligible patients are aged 18-70 years with previously-untreated histologically-proven CD20-positive stage II-IV MCL (all subtypes), ECOG 0-1, and no comorbidities precluding ASCT. Patient with major contraindications to BTKi use are excluded. Treatment is delivered in a unique and innovative acalabrutinib 'sandwich' design to avoid excess toxicity of combination acalabrutinib-chemoimmunotherapy (see figure). All patients receive 2 cycles of induction rituximab (R) 375 mg/m 2 IV (day 1) & acalabrutinib (A) 100mg BD PO daily (continuous) 4-weekly, followed by 4 conventional R-DHAOx chemoimmunotherapy cycles. Patients then undergo positron emission tomography (PET) assessment. Those with partial or complete response will proceed to carmustine, etoposide, cytarabine and melphalan (BEAM) autograft which is followed by A+R maintenance (A; 100 mg BD continuous for 1 year & R; 375 mg/m 2 IV, 3-monthly x 8 cycles). Patients with stable or progressive disease will be taken off st

[Formula presented] Introduction Central nervous system relapse (secondary central nervous system lymphoma -SCNS) is an uncommon but devastating complication of aggressive B-cell lymphoma. Patients (Pts) with CNS-IPI 4-6 are at greatest risk (10.2% at 2 years). Intravenous high-dose methotrexate (HD-MTX) is widely used to mitigate SCNS risk but data supporting this practice are limited. Methods We performed a multicentre, retrospective study at 21 sites in Australia, Asia, North America and Europe. Chart or registry review was performed for consecutively diagnosed pts with diffuse large B-cell lymphoma (DLBCL) and CNS-IPI 4-6, high grade B-cell lymphoma (HGBL) with rearrangements of MYC+BCL2 and/or BCL6 and primary breast/testicular DLBCL irrespective of CNS-IPI. Pts were diagnosed between 2000-2020, 18-80 years at diagnosis, and treated with curative intent anti-CD20 based chemo-immunotherapy. Pts with CNS involvement at diagnosis were excluded. HD-MTX was defined as at least one cycle of intravenous MTX at any dose. Time to SCNS was calculated from date of diagnosis (all-pts), and from the end of frontline systemic lymphoma therapy, defined as 6x21 days from diagnosis (complete response (CR-pts)), until SCNS, systemic relapse, death, or censoring, whichever came first. Cumulative risk of SCNS was computed using the Aalen-Johansen estimator treating death and systemic relapses as competing events. Adjusted cumulative risks were obtained by using an inverse probability of treatment weighting approach. The average treatment effect was computed as the difference in adjusted 5-year risk of SCNS. Results - 2300 and 1455 pts were included in the all-pts and CR-pts analyses, respectively. Baseline demographics and details of therapy are summarised in Table 1. Except for a predominance of males, pts <=60 years and pts with ECOG 0-1 in the HD-MTX vs no HD-MTX groups, the demographics and treatments were well balanced. At a median follow up of 5.9 years (range 0.0-19.1) and

Background: BCR signaling mediated through Bruton's tyrosine kinase (BTK) plays a critical role in the development and maintenance of marginal zone lymphoma (MZL). BTK inhibitors have established activity in relapsed/refractory (R/R) MZL with the phase 2 study of ibrutinib demonstrating an objective response rate (ORR) of 48% (Noy et al. Blood. 2017;129:2224-2232). Zanubrutinib is a potent and highly specific next-generation BTK inhibitor designed with greater selectivity for BTK vs TEC- and EGFRfamily kinases, which are thought to be related to off-target toxicities. Therapeutic activity of zanubrutinib was established in an early-phase study (BGB-3111-AU-003) of 20 patients (pts) with R/R MZL demonstrating an ORR of 80%, with a complete response (CR) rate of 15%, and partial response (PR) rate of 65% (Tedeschi et al. EHA 2020, abstract 2804). Aim(s): To present initial efficacy and safety results in pts with R/R MZL enrolled in MAGNOLIA (BGB-3111-214). Method(s): MAGNOLIA is a phase 2, multicenter, single-arm study of adults with R/R MZL who had received >=1 line of therapy including >=1 CD20-directed regimen. All were treated with zanubrutinib 160 mg twice daily until disease progression or unacceptable toxicity. Use of long-term antiplatelet and anticoagulation agents was permitted. The primary end point was ORR determined by an independent review committee in accordance with the Lugano classification. Secondary end points include ORR by investigator assessment, duration of response (DOR), progression-free survival (PFS), and safety. Result(s): As of January 11, 2021, 68 pts were enrolled and treated. Median age was 70 years (range, 37-95), with 28% aged >=75 years. Subtypes included extranodal (mucosa-associated lymphoid tissue; 38%), nodal (38%), splenic (18%), and indeterminate (6%) MZL. Median number of prior therapies was 2 (range, 1-6) and 32% of pts had disease that was refractory to last therapy. Median duration of drug exposure was 59.1 weeks (range, 3.

Primary cutaneous lymphomas represent a heterogeneous group of T- and B-cell lymphomas with distinct clinical presentations, histopathologic features, treatment approaches and outcomes. The cutaneous T-cell lymphomas, which include mycosis fungoides and Sézary syndrome, account for the majority of the cutaneous lymphomas. This Clinical Practice Statement is reflective of the current clinical practice in Australia. An expanded form of the Clinical Practice Statement (and updates), along with helpful patient resources and access to support groups, can be found at the following (http://www.australasianlymphomaalliance.org.au).

Primary cutaneous lymphomas represent a heterogeneous group of T- and B-cell lymphomas with distinct clinical presentations, histopathologic features, treatment approaches and outcomes. The cutaneous T-cell lymphomas, which include mycosis fungoides and Sezary syndrome, account for the majority of the cutaneous lymphomas. This Clinical Practice Statement is reflective of the current clinical practice in Australia. An expanded form of the Clinical Practice Statement (and updates), along with helpful patient resources and access to support groups, can be found at the following (http://www.australasianlymphomaalliance.org.au).Copyright © 2020 The Australasian College of Dermatologists

The role of cytarabine-based induction and autologous stem cell transplantation (ASCT) in front-line treatment of younger patients with mantle cell lymphoma (MCL) is well established, however the utility of intensive approaches in older patients remains unclear. This retrospective study compared first line treatment outcomes in patients aged 60 years or more, treated at six tertiary centres between 2000-2015. 70 patients included had a median age of 69 (60-91) and most (94%) demonstrated advanced stage disease. Treatment regimens included: R-CHOP-like (n=39), alternating R-CHOP/R-DHAC (n=10), R-HyperCVAD/R-MA (n=7), R-CHOP/Cytarabine (Nordic Protocol) (n=10) and other (n=4). 16 patients underwent an ASCT. The median follow-up for surviving patients was 37 months. Compared to R-CHOP-like therapies, cytarabine-based regimens were associated with an improved overall response rate (ORR) of 70% vs 33% (p<0.001) and overall survival (OS) (HR 0.541, [0.292-1.001], p=0.05). No difference in efficacy between different cytarabine-based regimens was detected, but R-HyperCVAD/R-MA was associated with increased hospitalisation and transfusion requirements. Patients undergoing ASCT demonstrated an improved median OS (HR 0.108 [0.015-0.796], p=0.029) but were significantly younger. These results reaffirm the use of cytarabine in MCL for selected patients aged over 60. Such regimens should be strongly considered for this population in frontline therapy.

Background: Grade 3B Follicular lymphoma (G3BFL) comprises approximately 15% of FL and controversy exists over whether it follows the relapsing/remitting course of low-grade FL, or more closely resembles diffuse large B cell lymphoma (DLBCL), which is potentially curable. Thus it is largely excluded from clinical trials for either group, hence robust data and management consensus are lacking. Aim(s): To establish survival outcomes of G3BFL. Method(s): We performed an international retrospective study of patients aged > / = 18 years, with G3BFL from tertiary institutions in Australia, Canada and England. Pure G3B, composite Grade 3A/G3BFL and G3BFL/ DLBCL treated with rituximab (R) or obinutuzumab (O) + chemotherapy +/- radiotherapy (RT) or RT alone between 2002-2019 were included. FL grading was according to WHO criteria. A comparator DLBCL group, treated with R-CHOP +/- radiotherapy from 2012-2018 was identified using the same criteria from 2 Australian sites. OS was defined as the time from the date of diagnosis until death from any cause; PFS was defined from diagnosis until relapse/progression (to any B cell lymphoma subtype) or death; both were calculated according to the Kaplan-Meier method. Associations between prognostic factors and outcomes were analysed with log-rank tests and Cox proportional hazards models. Result(s): 161 G3BFL cases were evaluable. Histology was G3BFL in 84, G3A/G3B FL in 25, and G3B/DLBCL in 52 ("G3B" group). Median age was 62 (18-86) and 55% were male. 71% of patients had stage III/ IV disease. 58% had a high FLIPI score. Treatment was R or O-CHOPlike chemotherapy +/- RT in 96% of cases with RT alone or BR in the remainder (2% each). 90% received anthracyclines. 171 DLBCL comparator cases were included with a median age of 68 years (25-91) and a high R-IPI in 54%. Compared to the G3B group, there was a statistically significant difference in age > 60 years (G3B: 53%, DLBCL 71%; P = 0.001), ECOG performance status > 2 (G3B 5%, DLBCL 23

INTRODUCTION: Cancer-related cognitive impairment (CRCI) is a distressing and disabling side-effect of cancer treatments affecting up to 75% of patients. For some patients, their cognitive impairment may be transient, but for a subgroup, these symptoms can be long-standing and have a major impact on the quality of life. This paper describes the protocol for a study: (1) to assess the feasibility of collecting longitudinal data on cognition via self-report, neuropsychological testing, peripheral markers of inflammation and neuroimaging and (2) to explore and describe patterns of cancer-related cognitive impairment over the course of treatment and recovery in patients with newly diagnosed, aggressive lymphoma undergoing standard therapy with curative intent. METHODS AND ANALYSIS: This is a prospective, longitudinal, feasibility study in which 30 newly diagnosed, treatment-naive patients with aggressive lymphoma will be recruited over a 12-month period. Patients will complete comprehensive assessments at three time points: baseline (time 1, pre-treatment) and two post-baseline follow-up assessments (time 2, mid-treatment and time 3, 6-8 weeks post-treatment completion). All patients will be assessed for self-reported cognitive difficulties and objective cognitive function using Stroop Colour and Word, Trail Making Test Part A and B, Hopkins Verbal Learning Test-Revised, Controlled Oral Word Association and Digit Span. Blood cell-based inflammatory markers and neuroimaging including a positron emission tomography (PET) with 18F-labelled fluoro-2-deoxyglucose (18F-FDG) and CT (18F-FDG-PET/CT) and a MRI will explore potential inflammatory and neuroanatomical or functional mechanisms and biomarkers related to CRCI. The primary intent of analysis will be to assess the feasibility of collecting longitudinal data on cognition using subjective reports and objective tasks from patients during treatment and recovery for lymphoma. These data will inform the design of a larger-sca

Transported probability density function (TPDF) methods are attractive for modeling turbulent flames as the highly nonlinear chemical reactions appear in closed form. The ability of the TPDF methods to capture complex phenomena such as extinction and re-ignition has been well demonstrated for turbulent non-premixed flames. However challenges remain when applying the TPDF methods to turbulent premixed flames, for which modeling molecular diffusion is difficult because the local species gradients may be strongly influenced by chemical reactions. The specification of a constant mechanical-to-scalar timescale ratio to relate the scalar mixing timescale to the turbulence timescale is questionable for premixed flames in the flamelet regime. In this paper, recent progress on scalar mixing is reviewed with particular focus on the analysis and modeling of the scalar mixing timescales in turbulent premixed flames using direct numerical simulation (DNS) datasets. The scalar dissipation rate of the progress variable from temporally evolving turbulent lean premixed H2-air flames in the thin reaction zone regime is analyzed using the chemical explosive mode analysis to understand its dependence on combustion modes and transient flame features. Moreover, models for the mixing timescale of the progress variable are discussed, with a focus on a recently developed hybrid mixing timescale model. This work concludes with a discussion on modeling differential diffusion in turbulent premixed flames.

Management practices in early-stage (I/II) follicular lymphoma (FL) are variable and include radiation (RT), systemic therapy, or combined modality therapy (CMT). There is a paucity of data regarding maintenance rituximab in this cohort. We conducted an international retrospective study of patients with newly diagnosed early-stage FL staged with positron emission tomography (PET)-computed tomography and bone marrow biopsy. Three hundred sixty-five patients (stage I, n 5 221), median age 63 years, treated from 2005-2017 were included, with a median follow-up of 45 months. Management included watchful waiting (WW; n 5 85) and active treatment (n 5 280). The latter consisted of RT alone (n 5 171) or systemic therapy (immunochemotherapy [n 5 63] or CMT [n 5 46]). Forty-nine systemically treated patients received maintenance rituximab; 72.7% of stage I patients received RT alone, compared to 42.6% with stage II (P, .001). Active therapies yielded comparable overall response rates (P 5 .87). RT alone and systemic therapy without maintenance rituximab yielded similar progression-free survival (PFS) (hazard ratio [HR], 1.32; 95% confidence interval [CI], 0.77-2.34; P 5 .96). Maintenance rituximab improved PFS (HR, 0.24; 95% CI, 0.095-0.64; P 5 .017). The incidence of transformation was lower with systemic therapy compared to RT or WW (HR, 0.20; 95% CI, 0.070-0.61; P 5 .034). Overall survival was similar among all practices, including WW (P 5 .40). In the largest comparative assessment of management practices in the modern era, variable practices each resulted in similar excellent outcomes. Randomized studies are required to determine the optimal treatment in early-stage FL.Copyright © 2019 by The American Society of Hematology

Non-Hodgkin lymphoma (NHL) encompasses a genomically heterogeneous group of diseases; some subtypes may be characterised by somatically acquired variants. There is increasing evidence genomic and/or transcriptomic characterisation of NHL informs better patient management, but a health economic argument is required to justify inclusion in routine clinical practice. The Melbourne Genomics Health Alliance Lymphoma flagship, a collaboration between three Melbourne-based health services, investigated the role of exome sequencing in the management of aggressive or poor prognosis Non-Hodgkin lymphoma. The flagship assessed variants leading to alterations of prognosis, diagnosis or therapy which would potentially lead to management changes, consistent with AMP/ASCO/CAP consensus guidelines. The flagship also investigated associated health economic implications. A total of 122 patients were enrolled on the flagship, of whom 91 (76%) were suitable for testing, the majority of testing exclusions were due to insufficient availability of template for testing, reinforcing the importance of pre-analytical sample collection aspects. Paired tumour/germline exomes were interrogated across 150 candidate genes including parallel copy number analysis. Limited orthogonal testing was conducted with a diagnostically accredited targeted sequencing panel and the Illumina 850K SNP microarray to confirm result validity. The majority of the cohort was comprised of de novo (44%) or transformed DLBCL (15%) cases. A mean of 10.6 somatic variants per patient were detected, of which 50% were classified as tier I variants. A number needed to test to potentially change management of <2 was calculated, health economic analysis is ongoing but early data is strongly supportive of routine use in clinical practice.Copyright © 2019

Mantle cell lymphoma (MCL) is an uncommon and typically aggressive form of lymphoma. Although often initially chemosensitive, relapse is common. Several induction and conditioning regimens are used in transplant-eligible patients, and the optimal approach remains unknown. We performed an international, retrospective study of transplant-eligible patients to assess impact of induction chemoimmunotherapy and conditioning regimens on clinical outcomes. We identified 228 patients meeting inclusion criteria. Baseline characteristics were similar among the induction groups except for some variation in age. The type of induction chemoimmunotherapy received did not influence overall response rates (ORRs) (0.43), progression-free survival (PFS) (P >.67), or overall survival (OS) (P >.35) on multivariate analysis (PFS and OS). Delivery of autologous stem cell transplant (ASCT) was associated with favorable PFS and OS (0.01) on univariate analysis only; this benefit was not seen on multivariate analysis-PFS (0.36) and OS (0.21). Compared with busulfan and melphalan (BuMel), the use of the carmustine, etoposide, cytarabine, melphalan (BEAM)-conditioning regimen was associated with inferior PFS (HR = 2.0 [95% CI 1.1-3.6], 0.02) but not OS (HR = 1.1 [95% CI 0.5-2.3], 0.81) on univariate analysis only. Within the limits of a retrospective study and modest power for some comparisons, type of induction therapy did not influence ORR, PFS, or OS for transplant-eligible patients with MCL. International efforts are required to perform randomized clinical trials evaluating chemoimmunotherapy induction regimens.Copyright © 2019 John Wiley & Sons, Ltd.

Background: DLBCL presenting with both CNS and systemic disease at first diagnosis is rare. Such patients are excluded from clinical trials; thus, the optimal treatment is unknown and outcomes are poorly described. Aim(s): To describe treatment outcomes of patients with synchronous CNS and systemic DLBCL at first diagnosis. Method(s):Multicentre retrospective international study (6 Australian & UK sites). Cases were identified from clinical and pharmacy records. Eligible patients had histologically proven DLBCL, with radiological, histological, or CSF evidence of synchronous systemic & CNS disease, treated with combination chemotherapy and rituximab. Patients with relapsed disease were excluded. Primary Endpoint: OS. Secondary endpoints: CR rate, PFS, toxicity. P values of <0.05 were considered significant. Result(s): Of 59 patients, 71% were male and the median age was 66yrs (range 17-86). 45 (76%) had NCCN-IPI >=4. Median number of extranodal sites outside the CNS was 2 (range 0-8). 10% were double-hit by FISH, and 35% of those with data available were double-expressors of MYC and BCL2 protein. CNS disease was leptomeningeal only in 24 (41%); 35 (59%) had parenchymal disease, 8 (14%) had both. 34 (58%) received systemic therapy (predominantly R-CHOP, n=31) plus a CNS-directed treatment (group A). 25 (42%) underwent intensified MTX and/or Ara-C containing therapy: hyper-CVAD n=14, CODOX-M/IVAC n=10, DHAC=1 (group B). CNS-directed therapy in group A included: IV HD-MTX in 19 (56%), HDMTX+ Ara-C in 2 (6%), intrathecal therapy (IT) only in 10 (29%), radiotherapy (RT) only in 2 (6%). Specific CNS therapy was omitted in one patient due to early PD. Additional consolidative therapy included CNS RT in 18 (31%) (whole brain in 8, site-specific in 10), and autologous SCT in CR1 in 8 (13%) using BEAM (n=4) or BCNU+thiotepa (n=4) conditioning. All SCT patients were from group B. 23 (39%) required dose reductions and 23 (39%) required early cessation of therapy. Treatment-rela

In the present work, nonpremixed temporally evolving planar spray jet flames are simulated using both direct numerical simulation (DNS) and the composition transported probability density function (TPDF) method. The objective is to assess the performance of various mixing and evaporation source term distribution models which are required to close the PDF transport equation in spray flames. Quantities which would normally be provided to the TPDF solver by spray models and turbulence models are provided from the DNS: the mean flow velocity, turbulent diffusivity, mixing frequency, and cell-mean evaporation source term. Two cases with different Damköhler numbers (Da) are considered. The low Da case (Da-) features extinction followed by reignition while extinction in the high Da case (Da+) is insignificant. The TPDF modelling considers two mixing models: interaction by exchange with the mean (IEM) and Euclidean minimum spanning trees (EMST). Three models for distribution of the evaporation source terms are considered: EQUAL which distributes them in proportion to notional particles' mass weight, NEW which creates new particles of pure fuel, and SAT which distributes the sources preferentially to notional particles close to saturation. It is found that the IEM model overpredicts the extinction when used with any evaporation model for both Da- and Da+ cases. The EMST model captures well the trend for extinction and reignition for the Da- case when it is coupled with the EQUAL evaporation model, but it overpredicts the extinction when coupled with the NEW or SAT evaporation model. For the Da+ case, all evaporation models reasonably capture the flame dynamics when coupled with EMST. The flame temperature in the mixture fraction space was examined to further assess the model performance. In general the EMST model results in narrow PDFs with little conditional fluctuation, while the IEM model produces bimodal PDFs with burning and partial extinction branches.

Background Stage I/II or early-stage follicular lymphoma (ESFL) is considered potentially curable with radiotherapy (XRT). While XRT does achieve local disease control in >90% of cases, more than half the patients (pts) relapse by 10 years (yr), generally outside of the radiation field. A recent randomized controlled trial (TROG 99.03) demonstrated that combined modality therapy (CMT), with sequential XRT and systemic therapy, significantly improved PFS but not overall survival (OS) compared to XRT alone in ESFL. However, only half the pts were staged with F-FDG positron emission tomography and computed tomography (PET) and 58% of CMT pts did not receive rituximab.Compared with CT staging, 20-60% of cases are upstaged by PET. Consequentially, there are limitations in applying this trial to modern populations. Despite the support of current guidelines, only one third of pts in clinical practice are treated with XRT. This suggests a need to better understand the role of other treatments, including watchful waiting (WW), in the PETera. Our aim was to compare outcomes with real-world treatment approaches in rigorously staged ESFL patients. Methods We conducted an international, multicenterretrospective study of stage I and II FL pts rigorously staged with bone marrow biopsy and PET. Eligible pts were >18yr with newly-diagnosed grade 1-3A FL and >=3 months follow up. Primary outcome measures were overall response rate (ORR), progression free survival (PFS), OS and risk of transformation. Survival curves were estimated with the Kaplan-Meier method and uni- and multivariate analysis was performed using Cox regression model. Results A total of 387 pts treated at 13 Australian and 3 Canadian centres between 2005-2017 were studied. Median follow-up was 45 months (range 3.1 - 164.0).5-yrPFS and OS rates were 73.5% (95% CI 66.0-78.5) and 94.4% (95% CI 89.4-93.6) respectively. 22 patients had stage IE duodenal FL with 5- yr PFS and OS rates of 100% and 100% respectively. Conside

The role of cytarabine-based induction and autologous stem cell transplantation (ASCT) in front-line treatment of younger patients with mantle cell lymphoma (MCL) is well established, however the utility of intensive approaches in older patients remains unclear. This retrospective study compared first line treatment outcomes in patients aged 60 years or more, treated at six tertiary centres between 2000–2015. 70 patients included had a median age of 69 (60–91) and most (94%) demonstrated advanced stage disease. Treatment regimens included: R-CHOP-like (n = 39), alternating R-CHOP/R-DHAC (n = 10), R-HyperCVAD/R-MA (n = 7), R-CHOP/Cytarabine (Nordic Protocol) (n = 10) and other (n = 4). 16 patients underwent an ASCT. The median follow-up for surviving patients was 37 months. Compared to R-CHOP-like therapies, cytarabine-based regimens were associated with an improved overall response rate (ORR) of 70% vs 33% (p < 0.001) and overall survival (OS) (HR 0.541, [0.292–1.001], p = 0.05). No difference in efficacy between different cytarabine-based regimens was detected, but R-HyperCVAD/R-MA was associated with increased hospitalisation and transfusion requirements. Patients undergoing ASCT demonstrated an improved median OS (HR 0.108 [0.015–0.796], p = 0.029) but were significantly younger. These results reaffirm the use of cytarabine in MCL for selected patients aged over 60. Such regimens should be strongly considered for this population in frontline therapy.

Mantle cell lymphoma (MCL) is an uncommon and typically aggressive form of lymphoma. Although often initially chemosensitive, relapse is common. Several induction and conditioning regimens are used in transplant-eligible patients, and the optimal approach remains unknown. We performed an international, retrospective study of transplant-eligible patients to assess impact of induction chemoimmunotherapy and conditioning regimens on clinical outcomes. We identified 228 patients meeting inclusion criteria. Baseline characteristics were similar among the induction groups except for some variation in age. The type of induction chemoimmunotherapy received did not influence overall response rates (ORRs) (0.43), progression-free survival (PFS) (P > .67), or overall survival (OS) (P > .35) on multivariate analysis (PFS and OS). Delivery of autologous stem cell transplant (ASCT) was associated with favorable PFS and OS (0.01) on univariate analysis only; this benefit was not seen on multivariate analysis-PFS (0.36) and OS (0.21). Compared with busulfan and melphalan (BuMel), the use of the carmustine, etoposide, cytarabine, melphalan (BEAM)-conditioning regimen was associated with inferior PFS (HR = 2.0 [95% CI 1.1-3.6], 0.02) but not OS (HR = 1.1 [95% CI 0.5-2.3], 0.81) on univariate analysis only. Within the limits of a retrospective study and modest power for some comparisons, type of induction therapy did not influence ORR, PFS, or OS for transplant-eligible patients with MCL. International efforts are required to perform randomized clinical trials evaluating chemoimmunotherapy induction regimens.

The present study explores the effect of in-cylinder generated non-thermal plasma on hydroxyl and soot development. Plasma was generated using a newly developed Microwave Discharge Igniter (MDI), a device which operates based on the principle of microwave resonation and has the potential to accentuate the formation of active radical pools as well as suppress soot formation while stimulating soot oxidation. Three diagnostic techniques were employed in a single-cylinder small-bore optical diesel engine, including chemiluminescence imaging of electronically excited hydroxyl (OH), planar laser induced fluorescence imaging of OH (OH-PLIF) and planar laser induced incandescence (PLII) imaging of soot. While investigating the behaviour of MDI discharge under engine motoring conditions, it was found that plasma-induced OH∗ signal size and intensity increased with higher in-cylinder pressures albeit with shorter lifetime and lower breakdown consistency. Results also indicated that a decreasing pressure gradient extends the lifetime of plasma-induced OH∗ signals while an increasing pressure gradient suppresses plasma-induced OH∗ formation and increases the rate of signal decay. Studies on the effect of MDI at the start of high temperature reaction when plasma is discharged during the ignition delay phase were also carried out. Despite plasma-induced OH∗ signals being detected from the motoring experiments, no significant difference in OH∗ or OH-PLIF signals were observed under fuel injected conditions in comparison to the baseline case. However, PLII imaging revealed that discharging the MDI during the sooting period of combustion resulted in both suppressed formation and enhanced oxidation of soot. This effect became more prominent with the implementation of multiple pulse MDI discharge strategies, leading to significantly reduced soot over all crank angles.

This study applies particle image velocimetry (PIV) to an optical spark-ignition direct-injection engine in order to investigate the effects of fuel-injection on in-cylinder flow. Five injection timing combinations, each employing a stoichiometric 1:1 split ratio double-injection strategy, were analysed at an engine speed of 1200 RPM and an intake pressure of 100 kPa. Timings ranged from two injections in the intake stroke to two injections in the compression stroke, resulting in a variety of in-cylinder environments from well-mixed to highly turbulent. PIV images were acquired at a sampling frequency of 5 kHz on a selected swirl plane. The flow fields were decomposed into mean and fluctuating components via two spatial filtering approaches — one using a fixed 8 mm cut-off length, and the other using a mean flow speed scaled cut-off length which was tuned in order to match the turbulent kinetic energy (TKE) profile of a 300 Hz temporal filter. From engine performance tests, the in-cylinder pressure traces, indicated mean effective pressure (IMEP), and combustion phasing data showed very high sensitivity to injection timing variations. To explain the observed trend, correspondence between the measured flow and these performance parameters was evaluated. An expected global trend of increasing turbulence with retarded injection timing was clearly observed; however, relationships between TKE and burn rate were not as obvious as anticipated, suggesting that turbulence is not the predominant factor associated with injection timing variations which impacts engine performance. Stronger links were observed between bulk flow velocity and burn rate, particularly during the early stages of flame development. Injection timing was also found to have a significant impact on combustion stability, where it was observed that low-frequency flow fluctuation intensity revealed strong similarities with the coefficient of variance (CoV) of IMEP, suggesting that these fluctuations are a su

The present study aims to evaluate the effects of engine speed on gasoline compression ignition (GCI) combustion implementing double injection strategies. The double injection comprises of near-BDC first injection for the formation of a premixed charge and near-TDC second injection for the combustion phasing control. The engine performance and emissions testing of GCI combustion has been conducted in a single-cylinder light-duty diesel engine equipped with a common-rail injection system and fuelled with a conventional gasoline with 91 RON. The double injection strategy was investigated for various engine speeds ranging 1200~2000 rpm and the second injection timings between 12°CA bTDC and 3°CA aTDC. From the tests, GCI combustion shows high sensitivity to the second injection timing and combustion phasing variations such that the advanced second injection causes advanced combustion phasing and extended pre-combustion mixing time, and thereby increasing engine efficiency and decreasing ISFC. This leads to the reduced smoke/ uHC/CO emissions but increased combustion noise and NOx emissions, similar to the trends in conventional diesel combustion. It is found that the increased engine speed requires a higher fuel mass per injection to maintain similar IMEP values, leading to lower efficiency, higher ISFC, and increased combustion noise. The heat release rate increases with increasing engine speed but the combustion phasing is largely unchanged. A typical smoke-NOx trade-off is found with increased smoke and decreased NOx emissions at higher engine speed, primarily due to reduced charge premixing time, which suggests the partially premixed charge-based GCI combustion behaves similar to conventional diesel combustion with overall lower smoke and NOx emissions.

A two-color pyrometry technique was applied to acquire spatially and temporally resolved soot temperature and soot distribution information of a main-post injection case, with a main to post injection mass ratio of 80% to 20% and a dwell time value of 1.5 ms, respectively. The measurements were performed in a quiescent steady environment of 19.4 kg/m3 ambient density, 5.1 MPa ambient pressure, 900 K bulk temperature and 15 vol.% O2 ambient concentration, inside a constant-volume combustion chamber (CVCC). A canola-based biodiesel was used for the experiments. The results reveal that for the test conditions of this study, the post injection is found to interact with the hot combustion gases at the tail of the main injection event, to ignite with a shorter ignition delay, and at a spatial location that is closer to the fuel injector. The combustion of the post injection event is observed to initiate and develop more rapidly, and at higher temperatures, when compared with that of the main injection event at equivalent injection timing. The soot concentration values of the post injection are also found to be lower and have a narrower distribution, when compared with the main injection.

Post-injection has shown significant benefits in the reduction of combustion emissions and soot formation from compression-ignition engines. However, there is a need to better understand the mechanisms underpinning the pollutant emission reduction, so that this injection strategy can be fully optimized. An experimental investigation was performed to understand the impact of dwell time on the interaction between the main and post injections for main-post injection cases. The measurements were performed in the quiescent steady environment inside a constant-volume combustion chamber (CVCC) of 19.4 kg/m3 ambient density, 5.1 MPa ambient pressure, 900 K bulk temperature and 15 vol.% O2 ambient conditions. A mass ratio of the main to post injection of 80% to 20% and a fixed injection pressure of 100 MPa were used. Main-post combustion properties were characterized from the high-speed flame luminosity imaging of the combustion cases. The results indicate that for the investigated test conditions, the ignition delay and location of the post injection increased with increasing dwell time. The flame luminosity of the post injection was observed to vary, depending on the dwell time used. The results indicate that the changes in the ignition and combustion characteristics were mainly driven by the extent of the interactions of the post injections with the combustion products originating from the mains.