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PDF file - 83K, JAK1 and JAK3 mutation status in NKTCL cases

PDF file - 110K, Non-synonymous somatic mutations identified in the Discovery set of four NKTCL cases

PDF file - 75K, Sequence analysis summary of tumor and blood samples from four NKTCL cases

PDF file - 74K, Primer sets used for Sanger sequencing and HRM analysis

PDF file - 185K, Representative HRM curves of a NKTCL case confirmed as heterozygous JAK3A573V mutation

In recent years, considerable progress has been made in the standard treatment for chronic lymphocytic leukaemia (CLL) due to the availability of new potent drugs. However, the majority of data on CLL were derived from Western populations, with limited studies and guidelines on the management of CLL from an Asian population perspective. This consensus guideline aims to understand treatment challenges and suggest appropriate management approaches for CLL in the Asian population and other countries with a similar socio-economic profile. The following recommendations are based on a consensus by experts and an extensive literature review and contribute towards uniform patient care in Asia.

Although combination therapy is the standard of care for relapsed/refractory non-Hodgkin’s lymphoma (RR-NHL), combination treatment chosen for an individual patient is empirical, and response rates remain poor in individuals with chemotherapy-resistant disease. Here, we evaluate an experimental-analytic method, quadratic phenotypic optimization platform (QPOP), for prediction of patient-specific drug combination efficacy from a limited quantity of biopsied tumor samples. In this prospective study, we enrolled 71 patients with RR-NHL (39 B cell NHL and 32 NK/T cell NHL) with a median of two prior lines of treatment, at two academic hospitals in Singapore from November 2017 to August 2021. Fresh biopsies underwent ex vivo testing using a panel of 12 drugs with known efficacy against NHL to identify effective single and combination treatments. Individualized QPOP reports were generated for 67 of 75 patient samples, with a median turnaround time of 6 days from sample collection to report generation. Doublet drug combinations containing copanlisib or romidepsin were most effective against B cell NHL and NK/T cell NHL samples, respectively. Off-label QPOP-guided therapy offered at physician discretion in the absence of standard options ( n = 17) resulted in five complete responses. Among patients with more than two prior lines of therapy, the rates of progressive disease were lower with QPOP-guided treatments than with conventional chemotherapy. Overall, this study shows that the identification of patient-specific drug combinations through ex vivo analysis was achievable for RR-NHL in a clinically applicable time frame. These data provide the basis for a prospective clinical trial evaluating ex vivo–guided combination therapy in RR-NHL.

This study aims to determine the relationship between Hounsfield Unit shift ( $\Delta {\mathrm{ HU}}$ ), tissue temperature change ( $\Delta T$ ), and tissue’s relative cross-sectional area change ( $\Delta A$ ) of ex vivo bovine liver tissues. The fresh bovine livers ( $n = 3$ ) were heated from 21 °C to 100 °C within 24 min using a custom-made ceramic hot plate and left for cooling to room temperature (~70 min). HU and tissue temperature measurement were obtained at 3-min intervals during the experiment. After that, the cross-sectional tissue area changes, and $\Delta A$ was calculated. Finally, a multivariate linear regression analysis was performed to determine the relationship between $\Delta {\mathrm{ HU}}$ , $\Delta T$ , and $\Delta A$ . The results were compared with that of the conventional $\Delta {\mathrm{ HU}}$ - $\Delta T$ linear model. Tissues that underwent a larger thermal dose experienced a higher degree of tissue contraction, an irreversible process that contributed to the non-linear behavior in the $\Delta {\mathrm{ HU}}$ - $\Delta T$ characteristic curve. This finding was in agreement with the histological test, in which the tissues nearer to the heat source had higher cell counts than those farther away. A phenomenological equation for $\Delta {\mathrm{ HU}}$ in the function of $\Delta T$ and $\Delta A$ shows better regression with the experimental data ( $R^{2} \in $ [0.838, 0.977]) than the conventional $\Delta {\mathrm{ HU}}$ - $\Delta T$ linear model. This finding indicates that tissue contraction is an important parameter to be considered in the development of CT thermometry. The $\Delta {\mathrm{ HU}}$ - $\Delta T$ - $\Delta A$ characteristic equation presented in this work offers accurate estimation of tissue temperature based on the HU change and magnitude of tissue contraction during a CT-guided thermal ablation procedure.

In this article, we proposed a laser hot needle for liver tissue tract ablation. The proposed laser hot needle is powered by a 4500-nm-diode laser incorporated with a closed-loop control system that comprises of a uniform fiber Bragg grating (FBG) temperature sensor and a computer. Based on the real-time feedback input from the FBG temperature sensor, the laser power is regulated by a proportional–integral–derivative (PID) control system to control the needle temperature. In the characterization test, a chirped grating-based distributed temperature sensor is employed for measuring the tissue temperature profile in the ex vivo bovine liver tissue during the ablation. A histological test is conducted to study the impact of tract ablation to the cellular structures of treated tissue and tissue coagulation. In a tract ablation test, a ~50-mm $\times \sim 6$ -mm (length $\times $ width) thermal denaturation zone has been created on ex vivo bovine liver tissue with the laser hot needle at 150 °C.

Alpha-fetoprotein (AFP) is an oncofetal glycoprotein that has been used as a tumor marker for hepatocellular carcinoma (HCC) in combination with ultrasound and other imaging modalities. Its utility is limited because of both low sensitivity and specificity, and discrepancies among the different methods of measurements. Moreover, its accuracy varies according to patient characteristics and the AFP cut-off values used. Combination of AFP with novel biomarkers such as AFP-L3, Golgi specific membrane protein (GP73) and des-gamma-carboxyprothrombin significantly improved its accuracy in detecting HCC. Increased AFP level could also signify severity of hepatic destruction and subsequent regeneration and is commonly observed in patients with acute and chronic liver conditions and cirrhosis. Hereditary and other non-hepatic disorders can also cause AFP elevation.

Contemporary data of peripheral T-cell lymphoma (PTCL) and natural-killer/T-cell lymphoma (NKTL) patients treated with ifosfamide, carboplatin and etoposide (ICE) are limited.We performed a retrospective analysis to estimate outcomes of ICE-treated PTCL and NKTL patients at three tertiary cancer centres in Singapore.Patients were identified through lymphoma databases from National Cancer Centre Singapore (NCCS), National University Hospital, Singapore (NUHS), and Singapore General Hospital (SGH). Responses and survival outcomes were determined from electronic medical records. A total of 75 patients with a median age of 50 were included. ICE was used as first-line treatment in 14 patients (19%) and as subsequent lines of treatment in 61 patients (81%). The overall response rates (ORR) for all patients was 63% (40% complete response [CR]). The ORR and CR in the first line were 86% and 64% respectively. At a median follow-up duration of 71.0 months, the median progression-free (PFS) and overall survival (OS) for all patients were 4.4 months (95%CI, 2.7-6.0) and 16 months (95%CI, 8.3-45.4) respectively.In summary, ICE showed high ORR but poor PFS in relapsed/refractory PTCL and NKTL. ORR of ICE in the first line setting appears better than real-world CHOP data and warrants further study.

Hepatitis C virus (HCV) is a significant cause of hepatocellular carcinoma (HCC). The direct-acting antivirals marked a new era of HCV therapy and are associated with greater than 95% cure rate. Successful treatment of chronic hepatitis C greatly reduces the risk of HCC. A proportion of patients, especially those with pre-existing cirrhosis, remain at risk for HCC despite sustained virologic response (SVR). Diabetes mellitus, hepatic steatosis, alcohol consumption and lack of fibrosis regression are associated with risks of HCC after HCV cure. Noninvasive modalities such as aspartate aminotransferase to platelet ratio index and fibrosis-4 index and transient elastography have been used to monitor hepatic fibrosis. More recently, various fibrosis scores have been combined with clinical parameters and other novel biomarkers to predict risks of HCC for patients who achieved SVR. These models still need to be validated and standardized prior to applying to routine clinical care.

Cutaneous T-cell lymphomas (CTCLs) are a group of T-cell lymphomas with low incidence. Due to their indolent characteristics, treatment strategies have not yet been established for advanced CTCLs. In this study, relative incidence of CTCLs in Asia was estimated and the therapeutic outcomes presented based on various treatments currently used in clinics for advanced CTCLs. As part of a prospective registry study of peripheral T-cell lymphoma (PTCL) conducted across Asia, including Korea, China, Taiwan, Singapore, Malaysia, and Indonesia, subgroup analysis was performed for patients with CTCLs. Among 486 patients with PTCL, 37 with CTCL (7.6%) were identified between April 2016 and February 2019. Primary cutaneous ALK-negative anaplastic large cell lymphoma (ALCL, 35.1%) was the most common subtype. With a median follow-up period of 32.1 months, median progression-free survival (PFS) was 53.5 months (95% CI 0.0–122.5), and overall survival was not reached. 14 patients (48.2%) underwent subsequent treatment after the first relapse, but the response rate was 20% with a PFS of 2.2 months (95% CI 0.3–4.0). Six patients received autologous stem cell transplantation (auto-SCT). However, auto-SCT did not result in better outcomes. Additional studies are needed on standard care treatment of advanced or refractory and relapsed CTCLs.

Background: Peripheral T-cell lymphomas (PTCLs) are uncommon and their incidence is regionally heterogeneous. Several studies have been conducted to evaluate the clinical features and treatment outcomes of this disease entity, but the majority of these were conducted in limited areas, making it difficult to comprehensively analyze their relative incidence and clinical features. Furthermore, no consensus treatment for PTCLs has been established. Therefore, we conducted an Asia-specific study to understand the relative incidence of PTCLs and assess treatments and their outcomes in Asian patients. Methods: We performed a multinational, multicenter, prospective registry of adult patients with PTCLs that was named as the International Cooperative non-Hodgkin T-cell lymphoma prospective registry study where thirty-two institutes from six Asian countries and territories (Korea, China, Taiwan, Singapore, Malaysia, and Indonesia) participated. Findings: A total of 486 patients were registered between April 2016 and February 2019, and more than a half of patients (57.4%) had stage III or IV. Extranodal natural killer (NK)/T- cell lymphoma was the most common subtype (n=139, 28.6%), followed by angioimmunoblastic T-cell lymphoma (AITL, n=120, 24.7%), PTCL-not otherwise specified (PTCL-NOS, n=101, 20.8%), ALK-positive anaplastic large cell lymphoma (ALCL, n=34, 6.9%), and ALK-negative ALCL (n=30, 6.2%) in decreasing order of frequency. The median progression-free survival (PFS) and overall survival (OS) were 21.1 months (95% CI,10.6–31.6) and 83.6 months (95% CI, 56.7–110.5), respectively. Upfront use of combined treatment with chemotherapy and radiotherapy showed better PFS than chemotherapy alone in localized ENKTL whereas consolidation with upfront autologous stem cell transplantation (SCT) provided longer PFS in advance stage ENKTL. In patients with PTCLs other than ENKTL, anthracycline-containing chemotherapies were widely used, but the outcome of those regimens was not satisfactory, and upfront autologous SCT was not significantly associated with survival benefit, either. The treatment outcome of salvage chemotherapy was disappointing, and none of the salvage strategies showed superiority to any other. Interpretation: This multinational, multicenter study identified the relative incidence of each subtype of PTCLs across Asian countries, and the survival outcomes according to the therapeutic strategies currently in use. Funding Statement: This study was supported by a grant from the Samsung Biomedical Research Institute (GFO1150161). Declaration of Interests: We declare no competing interests. Ethics Approval Statement: This registry was approved by the Institutional Review Boards or Scientific Review Committees as required by the policies of individual institutions. Written informed consent was obtained from each patient before study enrollment.

To investigate the efficacy of a newly-developed laser-heated core biopsy needle in the thermal ablation of biopsy tract to reduce hemorrhage after biopsy using in vivo rabbit's liver model.Five male New Zealand White rabbits weighed between 1.5 and 4.0 kg were anesthetized and their livers were exposed. 18 liver biopsies were performed under control group (without tract ablation, n = 9) and study group (with tract ablation, n = 9) settings. The needle insertion depth (~3 cm) and rate of retraction (~3 mm/s) were fixed in all the experiments. For tract ablation, three different needle temperatures (100, 120 and 150 °C) were compared. The blood loss at each biopsy site was measured by weighing the gauze pads before and after blood absorption. The rabbits were euthanized immediately and the liver specimens were stained with hematoxylin-eosin (HE) for further histopathological examination (HPE).The average blood loss in the study group was reduced significantly (p 0.05) compared to the control group. The highest percentage of bleeding reduction was observed at the needle temperature of 150 °C (93.8%), followed by 120 °C (85.8%) and 100 °C (84.2%). The HPE results show that the laser-heated core biopsy needle was able to cause lateral coagulative necrosis up to 14 mm diameter along the ablation tract.The laser-heated core biopsy needle reduced hemorrhage up to 93.8% and induced homogenous coagulative necrosis along the ablation tract in the rabbits' livers. This could potentially reduce the risk of tumor seeding in clinical settings.

Laparoscopic appendectomy (LA) is claimed to require less analgesic and allow for a faster return to work. This study examines whether these benefits hold true in Asian patient populations.A retrospective audit of emergency appendectomies over one year was conducted to study outcomes of postoperative pain, length of stay (LOS), duration of analgesia, and hospitalization leave (HL). A telephone questionnaire evaluated post-discharge analgesic intake, residual symptoms at follow-up, adequacy of HL and opinion on teleconsult reviews.Of the 201 patients, 187 (93%) underwent LA. Presurgery symptoms were significantly longer in the open appendectomy (OA) group (mean: OA 3.79, LA 1.81 days;Majority of LA patients do not need 2 weeks of analgesics and their HL can be shortened for faster return to work thereby realizing the true benefits of minimally invasive surgery. Selected cases can be offered postoperative teleconsultation.

A novel thermometric measurement based on chirped fiber Bragg grating (CFBG) and Michelson Interferometer is proposed. The interrogation technique is based on the linear relation between the temperature and the phase derivative function of the grating, which is determined through Fourier transformation of the output spectrum. The Michelson interferometer configuration offers the flexibility in adjusting the position of coupling coefficient curve in the spatiogram, enabling the interrogation to be done at a shorter optical spectrum record length which can reduce the interrogation time and computation load.

Predicated on our improved understanding of the disease biology, we have seen remarkable advances in the management of multiple myeloma over the past few years. Recently approved drugs have radically transformed the treatment paradigm and improved survivals of myeloma patients. The progress has necessitated revision of the diagnostic criteria, risk-stratification and response definition. The huge disparities in economy, healthcare infrastructure and access to novel drugs among different Asian countries will hinder the delivery of optimum myeloma care to patients managed in resource-constrained environments. In the light of the tremendous recent changes and evolution in myeloma management, it is timely that the resource-stratified guidelines from the Asian Myeloma Network be revised to provide updated recommendations for Asia physicians practicing under various healthcare reimbursement systems. This review will highlight the most recent advances and our recommendations on how they could be integrated in both resource-abundant and resource-constrained facilities.

Diffuse large B-cell lymphoma (DLBCL) is a high-grade lymphoma that requires treatment. We retrospectively analyzed the impact of time from diagnosis-to-treatment (TDT) on progression-free survival (PFS) and overall survival (OS) in 581 R-CHOP-treated patients. TDT was defined as the interval between diagnostic biopsy date and day 1 R-CHOP. Cox regression showed stage 3-4 disease (p = .01) and longer TDT (HR 1.13, p =.031) were associated with shorter OS. Eastern Cooperative Oncology Group ≥2 (p = .02), stage 3-4 disease (p

Introduction While combination therapy is the standard of care for relapsed/ refractory non-Hodgkin lymphoma (RR-NHL), the choice of combinations for an individual patient is empirical, and response rates remain poor. Here we explore the use of a hybrid experimental/analytic method termed Quadratic Phenotypic Optimization Platform (QPOP), for prediction of optimal drug combinations from limited clinical material. This high-throughput platform identifies optimal drug-combinations on ex-vivo biopsies using an orthogonal array composite design to maximise search space. These features are potentially useful to assess personalized efficacious combinations among a set of drugs with single agent pre-clinical or clinical activity in lymphoma. Methods We performed a prospective cohort study of QPOP analysis in RR-NHL. Participants included RR-NHL patients across two tertiary oncology centres in Singapore, with disease amenable to biopsy or blood/ marrow aspiration, recruited between 1 st November 2017 and 5 th May 2021 - with a median follow up of 24.5 months. CD20, CD3 or CD56 selection was performed to enrich for B, T or NK cells respectively, depending on the specimen type. QPOP drug combination scores were derived from lymphoma samples (approximately 1,000,000 cells/ patient) using a matrix of drugs with known pre-clinical or clinical efficacy against NHL. Results were shared with the treating physician, and off-label QPOP-guided therapy was offered in the absence of standard options. The primary outcomes were feasibility and turnaround time of QPOP analysis. The secondary outcomes were identification of recurrent 2 and 3 drug-combinations, and concordance of QPOP results with clinical responses. Results In this interim analysis period, we recruited 63 patients comprising 36 B-NHL and 27 T/NK-NHL, with a median age of 57 years and median 2 prior lines of treatment. Successful QPOP analysis (Z' score >0.5) was feasible in 56/63 cases with an average turn-around time of 6 (±2.1) days. QPOP predicted frequent sensitivities to Copanlisib- and Venetoclax-based combinations in B-NHL, and Romidepsin-based combinations in T/NK-NHL. Importantly, efficacy of specific combinations was not entirely dependent on single agent dose responses. Greater variability in ex-vivo responses was seen with combinations of targeted therapy and cytotoxic therapy compared with combinations of cytotoxic agents. Clinical responses were evaluable for 29 independent treatments in 26 patients. QPOP had a positive predictive value of 60% and a negative predictive value of 78.6% with an area under the curve of 0.672 (95%CI 0.47-0.87; p=0.12) for partial response or better (n=29, p= 0.06). Complete responses were achieved with novel QPOP derived drug combinations in patients refractory to standard therapy. Examples include Palbociclib-Everolimus for diffuse large B-cell lymphoma (figure 1) and Romidepsin-copanlisib for extra nodal natural killer T-cell lymphoma. Conclusions Prediction of sensitivity to drug-combinations in a clinically applicable time-frame is feasible for RR-NHL cases through QPOP analysis. The relatively small number of patients treated with QPOP directed regimens makes a definitive conclusion on concordance with clinical outcomes difficult at this stage. QPOP was however able to identify novel clinically effective combinations in patients refractory to standard therapy. These data provide the basis for a prospective clinical trial evaluating QPOP based therapy in RR-NHL. Figure 1 Figure 1. Disclosures Chng: Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Novartis: Honoraria; Abbvie: Honoraria. OffLabel Disclosure: everolimus palbociclib for diffuse large B cell lymphoma and rhomidepsin Bortezomib for extra nodal NK T cell lymphoma

// Thomas Sau-Yan Chan 1 , Yuh-Shan Lee 2 , Ilaria Del Giudice 3 , Marilisa Marinelli 3 , Caterina Ilari 3 , Luciana Cafforio 3 , Anna Guarini 4 , Daryl Tan 2 , Colin Phipps 2 , Yeow-Tee Goh 2 , William Hwang 2 , Allan Zhi-Kai Goh 2 , Lisa Lai-Ping Siu 5 , Saliangi Wu 6 , Chun-Yin Ha 7 , Shek-Ying Lin 8 , Chi-Hang Kwok 9 , Chi-Kuen Lau 10 , Kit-Fai Wong 5 , Robin Foa 3 , Yok-Lam Kwong 1 , Eric Tse 1 1 Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China 2 Department of Haematology, Singapore General Hospital, Outram, Singapore 3 Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy 4 Department of Molecular Medicine, Sapienza University, Rome, Italy 5 Department of Pathology, Queen Elizabeth Hospital, Hong Kong, China 6 Department of Medicine, Queen Elizabeth Hospital, Hong Kong, China 7 Department of Medicine, Tuen Mun Hospital, Hong Kong, China 8 Department of Medicine, United Christian Hospital, Hong Kong, China 9 Department of Medicine, Princess Margaret Hospital, Hong Kong, China 10 Department of Medicine, Tseung Kwan O Hospital, Hong Kong, China Correspondence to: Eric Tse, email: ewctse@hku.hk Keywords: chronic lymphocytic leukaemia, Chinese, pathological characteristics, clinical outcomes, prognostication Received: November 14, 2016 Accepted: February 13, 2017 Published: March 09, 2017 ABSTRACT Chronic lymphocytic leukaemia (CLL) is uncommon in Chinese population and its biology, genetics and treatment outcome in Chinese patients have not been comprehensively investigated. In this study, we studied the clinicopathological features and outcome of 212 Chinese patients with newly diagnosed CLL in Hong Kong and Singapore. The median age at diagnosis was 64 years. The majority of patients presented with early-stage disease (Binet stage A, 56.1%). Del(13)(q14) was the most frequent abnormality (41.7%) detected by fluorescence in situ hybridization (FISH) analysis. Del(17p) and TP53 gene mutations were detected in 7.8% and 8.2% of patients, respectively. MYD88 mutations were found at a higher frequency (11.5%) than expected. CLL with unmutated variable region of the immunoglobulin heavy chain genes ( IGHV ) occurred in only 31.2% of cases, and was associated with advanced-stage disease (p

This report serves as a snapshot of the state-of-knowledge in the Asia Pacific (APAC) Hematology Oncology community, and establishes a baseline for longitudinal investigations to follow changes in best practices over time. The objective of this study was to understand the approach to hematologic diseases, common standards of care and best practices, issues that remain controversial or debated, and educational or resource gaps that warrant attention. We used mobile application to disseminate and distribute questionnaires to delegates during the 6th international hematologic malignancies conference hosted by the APAC Hematology Consortium at Beijing, China. User responses were collected in an anonymous fashion. We report survey results in two ways: the overall responses, and responses as stratified between Chinese physicians and "Other" represented nationalities. Overall geographical concordance in survey responses was positive and strong. Perhaps more interesting than instances of absolute agreement, these data provide a unique opportunity to identify topics in which physician knowledge or opinions diverge. We assigned questions from all modules to broad categories of: patient information; diagnosis; treatment preference; transplantation; and general knowledge/opinion. On average, we observed a geographic difference of 15% for any particular answer choice, and this was fairly constant across survey modules. These results reveal utility and need for widespread and ongoing initiatives to assess knowledge and provide evidence-based education in real time. The data will be made more valuable by longitudinal participation, such that we can monitor changes in the state of the art over time.