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Background: Despite advances made in targeted biomarker-based therapy for acute myeloid leukemia (AML) treatment, remission is often short and followed by relapse and acquired resistance. Functional precision medicine (FPM) efforts have been shown to improve therapy selection guidance by incorporating comprehensive biological data to tailor individual treatment. However, effectively managing complex biological data, while also ensuring rapid conversion of actionable insights into clinical utility remains challenging., Methods: We have evaluated the clinical applicability of quadratic phenotypic optimization platform (QPOP), to predict clinical response to combination therapies in AML and reveal patient-centric insights into combination therapy sensitivities. In this prospective study, 51 primary samples from newly diagnosed (ND) or refractory/relapsed (R/R) AML patients were evaluated by QPOP following ex vivo drug testing., Results: Individualized drug sensitivity reports were generated in 55/63 (87.3%) patient samples with a median turnaround time of 5 (4-10) days from sample collection to report generation. To evaluate clinical feasibility, QPOP-predicted response was compared to clinical treatment outcomes and indicated concordant results with 83.3% sensitivity and 90.9% specificity and an overall 86.2% accuracy. Serial QPOP analysis in a FLT3-mutant patient sample indicated decreased FLT3 inhibitor (FLT3i) sensitivity, which is concordant with increasing FLT3 allelic burden and drug resistance development. Forkhead box M1 (FOXM1)-AKT signaling was subsequently identified to contribute to resistance to FLT3i., Conclusion: Overall, this study demonstrates the feasibility of applying QPOP as a functional combinatorial precision medicine platform to predict therapeutic sensitivities in AML and provides the basis for prospective clinical trials evaluating ex vivo-guided combination therapy., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

The digital revolution in healthcare, amplified by the COVID-19 pandemic and artificial intelligence (AI) advances, has led to a surge in the development of digital technologies. However, integrating digital health solutions, especially AI-based ones, in rare diseases like Waldenström macroglobulinemia (WM) remains challenging due to limited data, among other factors. CURATE.AI, a clinical decision support system, offers an alternative to big data approaches by calibrating individual treatment profiles based on that individual's data alone. We present a case study from the PRECISE CURATE.AI trial with a WM patient, where, over two years, CURATE.AI provided dynamic Ibrutinib dose recommendations to clinicians (users) aimed at achieving optimal IgM levels. An 80-year-old male with newly diagnosed WM requiring treatment due to anemia was recruited to the trial for CURATE.AI-based dosing of the Bruton tyrosine kinase inhibitor Ibrutinib. The primary and secondary outcome measures were focused on scientific and logistical feasibility. Preliminary results underscore the platform's potential in enhancing user and patient engagement, in addition to clinical efficacy. Based on a two-year-long patient enrollment into the CURATE.AI-augmented treatment, this study showcases how AI-enabled tools can support the management of rare diseases, emphasizing the integration of AI to enhance personalized therapy., (© 2024. The Author(s).)

Macrophages are abundant immune cells in the microenvironment of diffuse large B-cell lymphoma (DLBCL). Macrophage estimation by immunohistochemistry shows varying prognostic significance across studies in DLBCL, and does not provide a comprehensive analysis of macrophage subtypes. Here, using digital spatial profiling with whole transcriptome analysis of CD68+ cells, we characterize macrophages in distinct spatial niches of reactive lymphoid tissues (RLTs) and DLBCL. We reveal transcriptomic differences between macrophages within RLTs (light zone /dark zone, germinal center/ interfollicular), and between disease states (RLTs/ DLBCL), which we then use to generate six spatially-derived macrophage signatures (MacroSigs). We proceed to interrogate these MacroSigs in macrophage and DLBCL single-cell RNA-sequencing datasets, and in gene-expression data from multiple DLBCL cohorts. We show that specific MacroSigs are associated with cell-of-origin subtypes and overall survival in DLBCL. This study provides a spatially-resolved whole-transcriptome atlas of macrophages in reactive and malignant lymphoid tissues, showing biological and clinical significance., (© 2024. The Author(s).)

Deregulation of the DNA damage response (DDR) plays a critical role in the pathogenesis and progression of many cancers. The dependency of certain cancers on DDR pathways has enabled exploitation of such through synthetically lethal relationships e.g., Poly ADP-Ribose Polymerase (PARP) inhibitors for BRCA deficient ovarian cancers. Though lagging behind that of solid cancers, DDR inhibitors (DDRi) are being clinically developed for haematological cancers. Furthermore, a high proliferative index characterize many such cancers, suggesting a rationale for combinatorial strategies targeting DDR and replicative stress. In this review, we summarize pre-clinical and clinical data on DDR inhibition in haematological malignancies and highlight distinct haematological cancer subtypes with activity of DDR agents as single agents or in combination with chemotherapeutics and targeted agents. We aim to provide a framework to guide the design of future clinical trials involving haematological cancers for this important class of drugs., Competing Interests: AJ has received consultancy fees from Roche, Gilead, Turbine Ltd, AstraZeneca, Antegene, Janssen, MSD and IQVIA; and research funding from Janssen and AstraZeneca. SD has been on advisory boards for Amgen and Pfizer. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 De Mel, Lee, Tan, Tan, Poon, Chan, Lee, Chee, Lakshminarasappa, Jaynes and Jeyasekharan.)

Purpose: This systematic review, meta-analysis and meta-regression aimed to (1) evaluate the effects of resilience interventions on cancer patients' resilience and posttraumatic growth and (2) identify essential contents and features of resilience interventions., Methods: A systematic review, meta-analysis, and meta-regression analyses were conducted. Published and unpublished randomised controlled trials evaluating the effects of resilience interventions among cancer patients were retrieved from nine databases, trial registries, and grey literature. The mean and standard deviation scores were used to compute the effect sizes., Results: 23 randomised controlled trials comprising 3287 cancer patients were included. The random effects model found that resilience interventions had beneficial impacts on patients' resilience, posttraumatic growth, quality of life, anxiety, and depressive symptoms with moderate to large effects. The subgroup analyses concluded that theoretically guided interventions that adopted synchronous communication delivered physically had greater effect sizes. Interventions comprising skills that promote patients' cognitive flexibility, self-efficacy, self-esteem, self-regulation, and coping had greater effect in comparison with interventions lacking these components. The meta-regression analyses revealed that sample size has a significant effect on posttraumatic growth scores. More well-designed trials are needed to confirm the effects of resilience interventions., Conclusions: There is merit in utilizing resilience interventions to improve cancer patients' resilience and psychological well-being. Resilience interventions should be incorporated into the routine care for cancer patients and survivors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: A high incidence of venous thromboembolism (VTE) in COVID-19 has led to international recommendations for thromboprophylaxis. With limited data on Asian patients with COVID-19, the role of thromboprophylaxis remains unclear., Objectives: To investigate the in-hospital incidence of VTE in an Asian COVID-19 cohort, describe the VTE trend through successive COVID-19 waves (wild-type, delta, and omicron), and characterize the risk factors for VTE., Methods: We performed a retrospective observational cohort study of hospitalized COVID-19 adults from January 2020 to February 2022. Objectively confirmed VTE were reviewed to obtain VTE incidence and trend. Subset analysis of critical (intensive care), moderate (oxygen supplementation), and mild cases hospitalized ≥5 days was performed to investigate risk factors and in-hospital hazards of VTE., Results: Sixteen VTE events occurred among 3574 patients. Overall, VTE incidence was 0.45%, or 0.21% in mild, 3.60% in moderate, and 5.38% in critical infection. The maximum cumulative risk of VTE was 1.14% at 14 days for mild, 8.13% at 21 days for moderate, and 11.55% at 35 days for critical infection. Thromboprophylaxis use in mild, moderate, and critical cases was 5.7%, 28.8%, and 81.7%, respectively. In multivariable analysis, the severity of infection remained the strongest independent predictor of VTE. Compared with mild infection, the relative risk was 8.26 (95% CI, 2.26-30.16) for critical infection and 6.29 (95% CI, 1.54-25.67) for moderate infection., Conclusion: Overall, VTE incidence in Asian patients with COVID-19 is <1% across successive waves. Patients with moderate and critical infections are at greater risk for VTE and should be considered for routine thromboprophylaxis., (© 2023 The Author(s).)

Purpose of Review: The development of potent novel agents has improved outcomes for patients with multiple myeloma (MM). Heterogeneity of response to therapy, an expanding arsenal of treatment options, and cost are however major challenges for physicians making treatment decisions. Response-adapted therapy is hence an attractive strategy for sequencing of therapy in MM. Despite its successful application in other haematologic malignancies, response-adapted therapy is yet to become a standard of care for MM. We provide our perspective on response-adapted therapeutic strategies evaluated thus far and how they may be implemented and improved on in treatment algorithms of the future., Recent Findings: While older studies suggested that early response based on International Myeloma Working Group response criteria could impact long-term outcomes, recent data have contradicted these findings. The advent of minimal residual disease (MRD) as a powerful prognostic factor in MM has raised the promise of MRD-adapted treatment strategies. The development of more sensitive techniques for paraprotein quantification as well as imaging modalities to detect extramedullary disease is likely to change response assessment in MM. These techniques combined with MRD assessment may provide sensitive and holistic response assessments which could be evaluated in clinical trials. Response-adapted treatment algorithms have the potential to allow an individualised treatment strategy, maximising efficacy, while minimising toxicities and cost. Standardisation of MRD methodology, incorporation of imaging into response assessment, and the optimal management of MRD positive patients are key questions to be addressed in future trials., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Rituximab-based chemo-immunotherapy is currently the standard first-line treatment for Waldenstrom macroglobulinaemia (WM), while ibrutinib has emerged as an alternative. In the absence of randomised trials (RCTs) comparing these regimens, the optimal first-line treatment for WM remains uncertain. In this systematic review and meta-analysis, we sought to assess the efficacy and safety of first-line treatment regimens for WM. We searched key databases from January 2007 to March 2023, including phase II and III trials, including treatment-naïve WM patients treated with rituximab-based regimens or ibrutinib. Response rates, progression-free survival (PFS), overall survival (OS), and toxicities were evaluated. Four phase III and seven phase II trials were included among 736 unique records. Pooled response rates from all comparative and non-comparative trials were 46%, 33% and 26% for bendamustine rituximab (BR), bortezomib-dexamethasone, cyclophosphamide, rituximab (BDRC) and ibrutinib rituximab (IR), respectively. Two-year pooled PFS was 89%, 81% and 82% with BR, BDRC and IR, respectively. Neuropathy was more frequent with bortezomib, while haematologic and cardiac toxicities were more common with chemo-immunotherapy and ibrutinib-based regimens respectively. Our findings suggest that BR yields higher response rates than bortezomib or ibrutinib-based combinations. RCTs comparing BR against emerging therapies, including novel Bruton Tyrosine Kinase Inhibitors, are warranted., (© 2023. Springer Nature Limited.)

Background: There is currently no clinically validated biomarker to predict respiratory compromise in sudden acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Cycle threshold time (Ct), absolute lymphocyte count (AL) and neutrophil:lymphocyte ratio (NLR) have been previously evaluated for this purpose. We hypothesized that the combination of these parameters at presentation may be predictive of hypoxia (oxygen saturation <92%)., Methods: Data were collected on 118 patients with SARS-CoV-2 infection between May 2020 and April 2021. Demographics, clinical parameters and laboratory and radiological investigation results were recorded. Respiratory compromise (RC) was defined based on symptoms and signs, hypoxia and chest X-ray abnormalities., Results: RC occurred in 61 (51.7%) of patients. The Ct, AL and NLR at median day 3 of illness were significantly different between patients with and without RC (Ct, RC vs not: 19.46±2.64 vs 22.62±3.37, p=0.0001; AL, RC vs not: 531.49±289.09 vs 764.69±481.79, p=0.0001; NLR, RC vs not: 3.42±0.75 vs 2.59±0.55, p=0.0001). Receiver operating characteristics analysis showed that a Ct <19.9, AL <630.8×103/μL and NLR >3.12 at median day 3 of symptoms was predictive of hypoxia on day 7 of illness (area under the curve 0.805, sensitivity 96.7%, specificity 69.1%). The predictive value for the parameters combined was significantly superior to their individual predictive power., Conclusions: Ct, AL and NLR used in combination on day 3 of symptoms are predictive of hypoxia on day 7 of SARS-CoV-2 illness., (© The Author(s) 2021. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene.)

Background: There is a paucity of predictive factors for early recovery from thrombocytopenia related to dengue. The immature platelet fraction (IPF%) is reflective of megakaryopoiesis and may correlate with recovery from dengue-related thrombocytopenia. Our objective was to assess the predictive value of IPF% on days 2 and 3 of illness for recovery from dengue-related thrombocytopenia., Methods: A prospective study was conducted among patients with dengue admitted to our institution (Nawaloka Hospital PLC) from December 2019 to October 2020. Dengue was diagnosed based on positive non-structural antigen 1 or IgM. IPF% data were extracted from the Sysmex-XN-1000 automated hematology analyzer. Clinical data were obtained from electronic medical records. Statistical analyses were performed using SPSS version 20., Results: We included 240 patients. An IPF% on day 2 of illness of >7.15% had a sensitivity of 80.0% and specificity of 70.4% for prediction of platelet recovery (defined as platelet count ≥60×109/L) on day 7 of illness. An IPF% of >7.25% on day 3 of illness had a sensitivity of 88.9% and specificity of 47.1% for predicting platelet recovery >60×109/L on day 8 of illness. The IPF% was significantly lower in patients with severe dengue. Platelet recovery was observed within 48 h after the peak IPF% was reached, regardless of severity., Conclusion: We propose that IPF% values on days 2 and 3 of illness are a promising predictive tool for early recovery from dengue-related thrombocytopenia., (© The Author(s) 2021. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene.)

The role of central nervous system (CNS) prophylaxis with high-dose methotrexate (HDMTX) in DLBCL is controversial. In this retrospective study, we evaluated the efficacy of prophylactic HDMTX on isolated CNS relapse, concomitant CNS and systemic relapse, systemic relapse, and survival outcomes in 226 patients with newly diagnosed DLBCL and high-risk CNS International Prognostic Index (CNS-IPI) score treated with RCHOP. The three-year risk of isolated CNS relapse was significantly lower in patients who received HDMTX, at 3.1% compared to 14.6% (P = 0.032) in those who did not. However, neither concomitant CNS-systemic relapse rates, systemic relapse rates, nor three-year PFS and OS were significantly different between treatment groups in multivariable analysis. Among propensity score-matched patients (N = 102), HDMTX was also associated with significantly lower isolated CNS relapse rates (HR 0.06, 95% CI 0.004-0.946, P = 0.046). HDMTX was well tolerated with manageable toxicities when given at a dose of 3 g/m 2 by day 3 of RCHOP chemotherapy. Using propensity score matching and multivariable regression to yield treatment groups with well-balanced covariates, we showed that prophylactic HDMTX improved isolated CNS relapse rates but did not decrease concomitant CNS-systemic relapse rates, systemic relapse rates, or improve survival outcomes., (© 2021. The Author(s).)

Current prognostic scoring systems based on clinicopathologic variables are inadequate in predicting the survival and treatment response of extranodal natural killer/T-cell lymphoma (ENKTL) patients undergoing nonanthracyline-based treatment. We aimed to construct a classifier based on single-nucleotide polymorphisms (SNPs) for improving predictive accuracy and guiding clinical decision making. Data from 722 patients with ENKTL from international centers were analyzed. A 7-SNP-based classifier was constructed using LASSO Cox regression in the training cohort (n = 336) and further validated in the internal testing cohort (n = 144) and in 2 external validation cohorts (n = 142 and n = 100). The 7-SNP-based classifier showed good prognostic predictive efficacy in the training cohort and the 3 validation cohorts. Patients with high- and low-risk scores calculated by the classifier exhibited significantly different progression-free survival (PFS) and overall survival (OS) (all P < .001). The 7-SNP-based classifier was further proved to be an independent prognostic factor by multivariate analysis, and its predictive accuracy was significantly better than clinicopathological risk variables. Application of the 7-SNP-based classifier was not affected by sample types. Notably, chemotherapy combined with radiotherapy significantly improved PFS and OS vs radiotherapy alone in high-risk Ann Arbor stage I patients, whereas there was no statistical difference between the 2 therapeutic modalities among low-risk patients. A nomogram was constructed comprising the classifier and clinicopathological variables; it showed remarkably better predictive accuracy than either variable alone. The 7-SNP-based classifier is a complement to existing risk-stratification systems in ENKTL, which could have significant implications for clinical decision making for patients with ENKTL., (© 2021 by The American Society of Hematology.)

Multiple myeloma (MM) is an aggressive plasma cell neoplasm characterized by genomic heterogeneity. Superenhancers (SEs) are defined as large clusters of enhancers in close genomic proximity, which regulate genes for maintaining cellular identity and promote oncogenic transcription to which cancer cells highly addicted. Here, we analyzed cis-regulatory elements in MM samples with H3K27ac ChIP-seq, to identify novel SE-associated genes involved in the myeloma pathogenesis. SEs and their associated genes in cancerous tissue were compared with the control samples, and we found SE analysis alone uncovered cell-lineage-specific transcription factors and well-known oncogenes ST3GAL6 and ADM. Using a transcriptional CDK7 inhibitor, THZ1, coupled with H3K27ac ChlP-seq, we identified MAGI2 as a novel SE-associated gene of myeloma cells. Elevated MAGI2 was related to myelomagenesis with gradual increased expression from MGUS, SMM to newly diagnosed and relapsed MM. High prevalence of MAGI2 was also associated with poor survival of MM patients. Importantly, inhibition of the SE activity associated with MAGI2 decreased MAGI2 expression, inhibited cell growth and induced cell apoptosis. Mechanistically, we revealed that the oncogenic transcription factor, MAF, directly bound to the SE region and activated gene transcription. In summary, the discoveries of these acquired SEs-associated genes and the novel mechanism by which they are regulated provide new insights into MM biology and MAGI2-MAF-SE regulatory circuit offer potential novel targets for disease treatment.

Background: The early identification of patients at risk of severe dengue infection (DI) is critical to guide clinical management. Non-structural antigen 1 (NS-1), immunoglobulin M (IgM) and immunoglobulin G (IgG) are used routinely for the diagnosis of DI., Objectives: We sought to evaluate whether positivity for NS-1, IgM and IgG individually or together is predictive of severe complications of DI., Methods & Materials: A prospective study was conducted among patients with DI admitted to our institution between 2014 and 2019. DI was diagnosed based on a positive NS1 or IgM. IgG was also tested on all the patients. Clinical data was obtained from electronic medical records at NH. Statistical analyses were performed using SPSS version 20., Results: We collected data on 3504 patients. Patients who were positive for NS1, IgM and IgG (triple positive: TP) were more likely to develop severe DI (63.8 %) in comparison to those who were only NS1 positive (single positive: SP) (3.0 %) and patients with positive NS1 and IgM (double positive: DP) (7.5 %). [p = 0.001]. Regression analysis confirmed that TP status on admission was predictive of severe complications. (p < 0.01). Receiver operator characteristic curve (ROC) analysis showed (AUC: 84.8; sensitivity = 90.7 and specificity = 83.2) that TP status on admission is predictive of thrombocytopenia on day 5. The predictive power of TP status was superior to that of NS1 and IgG positivity., Conclusions: We propose that TP status on admission is a novel predictive factor for severe DI. Further studies are required to explore the biological basis for this finding., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: The treatment landscape for multiple myeloma (MM) has progressed significantly, and over the past decade, bortezomib-based induction therapy has been a standard of care. However, the practice of antibacterial prophylaxis during induction therapy has been diverse. The aim of our study is to evaluate the proportion of patients with febrile episodes and bacteremia among patients with MM, during the first 12 weeks of bortezomib-based induction therapy, without routine fluoroquinolone prophylaxis, but with routine Pneumocystis Carinii prophylaxis (mostly with trimethoprim-sulfamethoxazole), in a region with high fluoroquinolone resistance rate. Of note, these patients have direct access to health care facilities and timely supportive care., Patients and Methods: We evaluated newly diagnosed MM patients from 2014 to 2018 receiving bortezomib-based induction therapy for the proportion of patients who had febrile episodes and bacteremia in the first 12 weeks of bortezomib-based induction therapy. We also evaluated if there were factors associated with increased febrile episodes including age, absolute neutrophil count, creatinine clearance, M-band level at diagnosis, nadir platelet count, International Staging System, and Revised International Staging System., Results: Of the 108 evaluable patients, there were a total of 25 (23.1%) patients who had febrile episodes, and 1 (0.9%) patient who had bacteremia during the first 12 weeks of bortezomib-based induction therapy. All patients recovered well. No deaths were seen. Febrile episodes were associated with lower absolute neutrophil count (P = .036), renal impairment (P = .013), and ISS stage (P = .026)., Conclusion: The proportion of patients with significant bacterial infection during the first 12 weeks of bortezomib-based induction therapy without routine fluoroquinolone prophylaxis, but with routine Pneumocystis Carinii prophylaxis (mostly with trimethoprim-sulfamethoxazole), is low in a population with adequate access to health care facilities and timely supportive care., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: The Revised International Staging System (R-ISS) has been widely adopted to prognosticate multiple myeloma. As a result, the continued utility of conventional metaphase karyotyping has been called into question., Patients and Methods: A multi-center study for newly diagnosed patients with multiple myeloma who received novel agent(s) at induction was conducted. Conventional metaphase karyotype information was categorized based on ploidy. We evaluated the impact of ploidy on overall survival (OS) including multivariate analysis, taking into account the R-ISS stages, transplant status, age, and novel agent(s) used at induction. We also evaluated if it is possible to identify high-risk (HR) patients with conventional karyotyping when a fluorescence in situ hybridization analysis is not available. Results were validated in an independent cohort., Results: There were 308 patients evaluable. Ploidy significantly affected the OS of patients with R-ISS stage II, with non-hyperdiploid patients doing the worst. In the multivariate analysis, ploidy was significantly associated with OS. R-ISS stage II patients with or without non-hyperdiploid karyotype had significantly different survival. We replaced HR fluorescence in situ hybridization abnormalities with HR metaphase karyotypic abnormalities (non-hyperdiploid karyotype). When compared with R-ISS, there was a high level of concordance in HR patients identified using HR karyotypic abnormalities. These results were validated with an independent cohort of 375 patients., Conclusion: Conventional metaphase karyotyping is an independent prognostic factor even in the setting of R-ISS., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: High dose Cyclophosphamide (Cy) and Vinorelbine Cyclophosphamide (Vino-Cy) are stem cell (SC) mobilisation options for patients with multiple myeloma (MM). We present a comparison of mobilisation outcomes using these regimens., Patients and Methods: Vino-Cy patients received Vinorelbine 25 mg/m 2 on day 1, cyclophosphamide 1500 mg/m 2 on day 2, and pegylated GCSF on day 4 or GCSF 10 mcg/kg/day from day 4 onwards. Cy patients were given cyclophosphamide 4000 mg/m 2 on day 1 and GCSF10 mcg/kg/day from day 5 onwards. The target CD34 + SC collection was 5 × 10 6  per kg/BW., Results: 149 patients were included. SC collection was lower in the Vino-Cy group (8.20 × 10 6 /Kg BW) compared to the Cy group (11.43 × 10 6 /Kg BW), with adjusted geometric mean ratio of 0.59 (95% CI 0.41 to 0.86, p = 0.006). Time taken to achieve an adequate PB SC count was shorter for Vino-Cy (9 ± 1 day compared to 12 ± 2 days for Cy, adjusted absolute mean difference -3.95, 95% CI -4.85 to -3.06, P < .001). Mobilisation related toxicities (in particular, neutropaenic fever) were greater for Cy., Conclusion: Vino-Cy is a potential alternative to Cy given the need for effective mobilisation protocols with acceptable toxicity., (Copyright © 2018 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. All rights reserved.)

Immunohistochemistry (IHC) provides clinically useful information on protein expression in cancer cells. However, quantification of colocalizing signals using conventional IHC and visual scores is challenging. Here we describe the application of quantitative immunofluorescence in angioimmunoblastic T-cell lymphoma (AITL), a peripheral T-cell lymphoma characterized by cellular heterogeneity that impedes IHC interpretation and quantification. A multiplexed immunofluorescence (IF) panel comprising T- and B-lymphocyte markers along with T-follicular helper (T FH ) markers was validated for appropriate cellular localization in sections of benign tonsillar tissue and tested in two samples of AITL, using a Vectra microscope for spectral imaging and InForm software for analysis. We measured the percentage positivity of the T FH markers, BCL6 and PD1, in AITL CD4-positive cells to be approximately 26% and 45%, with 12% coexpressing both markers. The pattern is similar to CD4 cells within the germinal center of normal tonsils and clearly distinct from extragerminal CD4 cells. This study demonstrates the feasibility of automated and quantitative imaging of a multiplexed panel of cellular markers in formalin-fixed, paraffin-embedded tissue sections of a cellularly heterogenous lymphoma. Multiplexed IF allows the simultaneous scoring of markers in malignant and immune cell populations and could potentially increase accuracy for establishment of diagnostic thresholds.

Background: The current standard of care for transplant-eligible myeloma patients is novel agent-based induction, followed by high-dose chemotherapy and autologous stem cell rescue. Chemo-mobilization of peripheral blood CD34 + stem cells (PBSCs) with pegylated filgrastim (pegfilgrastim), a sustained-duration formulation of filgrastim, has been used as an alternative to filgrastim in several studies involving heterogeneous cohorts of lymphoma and multiple myeloma (MM) patients and shown to be equivalent in PBSC yield and cost-effectiveness. The present study focused on the efficacy of pegfilgrastim in PBSC mobilization compared with filgrastim exclusively after novel agent-based induction in a homogeneous group of MM patients., Patients and Methods: We analyzed the data from 89 patients with MM treated at 2 transplant centers in Singapore who had received novel agent-based induction chemotherapy, PBSC mobilization with vinorelbine/cyclophosphamide, high-dose melphalan conditioning, and autologous stem cell rescue. Of the 89 patients, 61 were included in the pegfilgrastim group and 28 in the filgrastim group, with a similar median age and disease characteristics. PBSC harvesting was performed at a similar median time of 9.51 ± 0.84 days for both, and the peak peripheral blood CD34 + stem cell count was 19.90 × 10 6 /kg for pegfilgrastim and 32.50 × 10 6 /kg for filgrastim (95% confidence interval, -4.36 to 0.70 × 10 6 /kg)., Results: No significant difference was found in the median PBSC collection between the 2 groups (pegfilgrastim, 7.90 × 10 6 /kg vs. filgrastim, 10.10 × 10 6 /kg; P = .16)., Conclusion: The present study has demonstrated that a single dose of pegfilgrastim is comparable to filgrastim in terms of the timing and efficacy of PBSC harvest and could potentially spare the patient 6 days of filgrastim injections. In addition, ours is the first study to compare these growth factors using vinorelbine/cyclophosphamide as mobilization chemotherapy., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Introduction: Bone marrow aspirate and trephine (BMAT) biopsy is a commonly performed procedure in hematology-oncology practice. Although complications are uncommon, they can cause significant morbidity and mortality. Simulation models are an excellent tool to teach novice doctors basic procedural skills before performing the actual procedure on patients to improve patient safety and well-being., Methods: There are no commercial BMAT simulators, and this technical report describes the rationale, technical specifications, and construction of a low-cost, easily constructed, reusable BMAT simulator that reproduced the tactile properties of tissue layers for use as a teaching tool in our resident BMAT simulation course. Preliminary data of learner responses to the simulator were also collected., Results: From April 2013 to November 2013, 32 internal medicine residents underwent the BMAT simulation course. Eighteen (56%) completed the online survey, 11 residents with previous experience doing BMAT and 7 without experience. Despite the difference in operative experience, both experienced and novice residents all agreed or strongly agreed that the model aided their understanding of the BMAT procedure. All agreed or strongly agreed that this enhanced their knowledge of anatomy and 16 residents (89%) agreed or strongly agreed that this model was a realistic simulator., Conclusions: We present a novel, low-cost, easily constructed, realistic BMAT simulator for training novice doctors to perform BMAT.