Cenozoic history of the tropical marine biodiversity hotspot.

The region with the highest marine biodiversity on our planet is known as the Coral Triangle or Indo-Australian Archipelago (IAA)1,2. Its enormous biodiversity has long attracted the interest of biologists; however, the detailed evolutionary history of the IAA biodiversity hotspot remains poorly understood3. Here we present a high-resolution reconstruction of the Cenozoic diversity history of the IAA by inferring speciation-extinction dynamics using a comprehensive fossil dataset. We found that the IAA has exhibited a unidirectional diversification trend since about 25 million years ago, following a roughly logistic increase until a diversity plateau beginning about 2.6 million years ago. The growth of diversity was primarily controlled by diversity dependency and habitat size, and also facilitated by the alleviation of thermal stress after 13.9 million years ago. Distinct net diversification peaks were recorded at about 25, 20, 16, 12 and 5 million years ago, which were probably related to major tectonic events in addition to climate transitions. Key biogeographic processes had far-reaching effects on the IAA diversity as shown by the long-term waning of the Tethyan descendants versus the waxing of cosmopolitan and IAA taxa. Finally, it seems that the absence of major extinctions and the Cenozoic cooling have been essential in making the IAA the richest marine biodiversity hotspot on Earth.

Clinical manifestations and risk factors for COVID-19 and its severity in patients with hematological malignancies.

BACKGROUND: Patients with hematological malignancies (HM) were at a high risk of developing severe disease from coronavirus disease 2019 (COVID-19). We aimed to assess the clinical outcome of COVID-19 in hospitalized patients with HM. METHODS: Adult patients with HM who were hospitalized with a laboratory-confirmed COVID-19 between May, 2021 and November, 2022 were retrospectively identified. Primary outcome was respiratory failure requiring mechanical ventilation or mortality within 60 days after hospitalization. We also analyzed associated factors for de-isolation (defined as defervescence with a consecutive serial cycle threshold value > 30) within 28 days. RESULTS: Of 152 eligible patients, 22 (14.5%) developed respiratory failure or mortality in 60 days. Factors associated with developing respiratory failure that required mechanical ventilation or mortality included receipt of allogeneic hematopoietic stem-cell transplantation (allo-HSCT) (adjusted hazards ratio [aHR], 5.10; 95% confidence interval [CI], 1.64-15.85), type 2 diabetes mellitus (aHR, 2.47; 95% CI, 1.04-5.90), lymphopenia at admission (aHR, 6.85; 95% CI, 2.45-19.15), and receiving <2 doses of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines (aHR, 3.00; 95% CI, 1.19-7.60). Ninety-nine (65.1%) patients were de-isolated in 28 days, against which two hazardous factors were identified: receipt of B-cell depletion therapies within one year prior to COVID-19 (aHR, 0.55, 95% CI, 0.35-0.87) and lymphopenia upon admission (aHR, 0.65; 95% CI, 0.43-1.00). CONCLUSION: We found a high rate of respiratory failure and mortality among patients with HM who contracted the SARS-CoV-2. Factors associated with developing respiratory failure or mortality in 60 days included receipt of allo-HSCT, type 2 diabetes mellitus and lymphopenia upon admission. Having received ≥2 doses of vaccination conferred protection against clinical progression.

Modified screening and management strategies for chronic rhinosinusitis in hematologic patients receiving hematopoietic stem cell transplantation.

OBJECTIVES: Given the lack of consensus on the screening and treatment for chronic rhinosinusitis (CRS) in the patients undergoing hematopoietic stem cell transplantation (HSCT), we reviewed the risk factors for CRS to improve the efficiency of sinonasal screening and analyzed the effect of treating CRS in search of guidance for modifying current management strategies for rhinosinusitis in HSCT patients. METHODS: We conducted a nested case-control study in a retrospective cohort of hematologic patients receiving HSCT from April 2011 to April 2021 and collected data on demographics, smoking/atopic status, hematological diseases, and features of rhinosinusitis for analysis. The associated factors for control of rhinosinusitis and survival were analyzed. RESULTS: Fifty-eight CRS patients were identified, and another 116 age- and sex-matched controls were selected from HSCT patients without CRS. Allergy and smoking were risk factors for CRS in HSCT patients. The multivariable logistic analysis indicated that endoscopic sinus surgery (ESS) was an independent factor for better control of CRS. However, survival was not associated with rhinosinusitis-related factors, but only with hematologic-related factors, including allogenic HSCT, reduced-intensity conditioning, and remission. CONCLUSIONS: Sinonasal evaluation should be targeted to the high-risk group. ESS is effective in managing CRS, while control of CRS is not determinant of overall survival in patients receiving HSCT.

Risk of thromboembolic events associated with different multiple myeloma regimens in Taiwan: a nested case-control study.

Although novel agents for multiple myeloma (MM) have a better response rate and survival in both newly diagnosed and relapsed/refractory MM patients, concerns regarding the association between MM treatments and thromboembolic events have been raised. The aim of this population-based study was to examine the association between different combinations of MM treatments and the risk of thromboembolic events. We conducted a nested case-control study using the Taiwan Cancer Registry (TCR) and National Health Insurance Research Database (NHIRD). Adult patients newly diagnosed with MM and treated with at least one of the immunomodulatory agents between 2008 and 2016 were identified. Among them, we further identified patients who developed thromboembolic events as cases and selected controls matched by age, sex and duration of MM diagnosis at a ratio of 1:5. The index date was defined as the day one year before the diagnosis date of thromboembolic events in the case group and the corresponding date in the control group. Conditional logistic regression was used to examine the association between different MM treatment regimens and the risk of thromboembolic events. A total of 4,180 newly diagnosed MM patients treated with at least one of the immunomodulatory agents were identified (mean age: 67.2 years; male: 55.7%). In this MM cohort, we further identified 388 cases and 1,940 matched controls (mean age: 71 years; male: 64.2%). The use of a thalidomide/bortezomib/steroid combination (odds ratio (OR) 2.95 [95% confidence interval (CI) 1.47-5.95]), thalidomide monotherapy (OR 3.33; 95% CI, 1.59-6.94), and a thalidomide/steroid combination (OR 4.24; 95% CI, 2.00-8.98) were associated with an increased risk of thromboembolic events. Other risk factors, particularly a history of thromboembolic events, including ischemic heart disease and pulmonary embolism, were significantly associated with increased risk of thromboembolic events. We found that the use of thalidomide alone and in specific combinations was associated with an increased risk of thromboembolic events.

Bone Marrow Histology in Hemophagocytic Lymphohistiocytosis.

CONTEXT.­: Bone marrow (BM) samples are obtained through aspiration and trephine biopsy. Hemophagocytic lymphohistiocytosis (HLH) has been largely studied in BM aspirate smears. OBJECTIVE.­: To investigate the histologic features of HLH in trephine biopsy. DESIGN.­: Patients with hemophagocytosis in BM aspirate smears were assigned to HLH (n = 127) and non-HLH (n = 203) groups. We quantified hematoxylin-eosin and CD68 immunohistochemical staining of their trephine biopsies. RESULTS.­: No significant correlation was noted in the hemophagocytosis count between aspirate smears and trephine biopsies. Compared with the non-HLH group, the HLH group had a higher hemophagocytosis count (13 versus 9 per tissue section, P = .046), lower percentage of the adipocytic area (36.7% versus 50.3%, P < .001), and higher percentage of the foamy area (19.1% versus 14.5%, P < .001). The HLH group had more histiocyte infiltrates (total histiocyte density, 9.2% versus 7.3%; P < .001) and more fat-infiltrating histiocytes (histiocyte density of the fat-associated part [HD-FA], 7.6% versus 6.2%; P < .001). We identified the following poor prognostic factors in the HLH group: age 50 years or older (median overall survival [mOS], 95 versus 499 days; P = .04), Epstein-Barr virus-positive T-cell lymphoproliferative diseases (EBV+TLPDs) (mOS, 51 versus 425 days; P < .001), hemophagocytosis count of 6 or higher per tissue section (mOS, 66 versus 435 days; P = .02), and HD-FA of 9% or greater (mOS, 61 versus 359 days; P = .02). Multivariate analysis revealed that age 50 years or older (hazard ratio [HR], 2.38; P < .001), EBV+TLPDs (HR, 2.07; P < .001), and hemophagocytosis count of 6 or higher per tissue section (HR, 2.07; P = .002) were independent prognostic factors for HLH. CONCLUSIONS.­: The HLH group had higher hemophagocytic activity, higher cellularity, a more foamy appearance, more histiocyte infiltrates, and more fat-infiltrating histiocytes. High hemophagocytic activity and marked histiocyte infiltrates in the BM fat were associated with poorer prognosis.

Management of metastatic renal cell carcinoma following prior vascular endothelial growth factor-targeted therapy: A real-world retrospective study from Taiwan.

BACKGROUND: There are limited real-world data to guide the sequencing of targeted therapies in patients with metastatic renal cell carcinoma (mRCC). The objective of this study was to characterize real-world treatment patterns (primarily second line [2L]) after prior vascular endothelial growth factor (VEGF) targeted therapy in an unselected mRCC population from Taiwan between 2013 and 2017. Treatment-related adverse events (TRAEs) and their management were also evaluated (NCT03633579). METHODS: This retrospective cohort study included patients who had received prior VEGF-targeted therapy and were treated at the National Taiwan University Hospital or the Taipei Veterans General Hospital between June 2013 and December 2017. Outcomes were characterized using descriptive statistics. RESULTS: Overall, 27 patients were included: 22 (81.5%) male; mean standard deviation (SD) age, 63.1 (11.1) years; 18 (66.7%) initiated targeted therapy during the year immediately following mRCC diagnosis. All patients received sunitinib as their first-line (1L) targeted therapy, with a median (range) treatment duration of 10 (1.8-65.8) months. The most common reason for discontinuing 1L sunitinib was disease progression (88.9% of patients). Everolimus was the most common 2L targeted therapy, in 23 patients (85.2%); 4 patients (14.8%) received 2L axitinib. Median (range) duration of 2L therapy was 4.0 (0.1-30.5) months for everolimus and 4.2 (0.5-9.2) months for axitinib. Ten TRAEs were reported among seven patients receiving 2L everolimus: hypertension (n = 5), hand-foot syndrome (n = 2), hyperglycemia (n = 1), renal failure (n = 1), and interstitial pneumonitis (n = 1). The majority (80%) of TRAEs were managed in the outpatient setting. No TRAEs were reported in the axitinib group. CONCLUSION: Real-world management of patients with mRCC in Taiwan broadly aligned with clinical guidelines and national reimbursement policy at the time of the study. These findings may be a useful reference for assessing the implications of evolving mRCC management approaches in Taiwan.

The epidemiology, treatment patterns, healthcare utilizations and costs of Acute Myeloid Leukaemia (AML) in Taiwan.

BACKGROUNDS: An increasing incidence of Acute Myeloid Leukaemia (AML) has been reported in several Western countries. However, the epidemiology of AML in Asia is very limited. According to the National Comprehensive Cancer Network (NCCN) guideline of AML, a range of conventional therapy options is available to AML patients. Nevertheless, different treatment strategies may result in diverse healthcare utilization and costs. Understanding the treatment patterns, healthcare utilization and costs of AML would thus be essential for clinicians and policymakers to optimize the treatment strategies of AML. OBJECTIVES: The objective of this study was to investigate the incidence, treatment patterns, healthcare utilization and costs of AML in Taiwan using a nationwide population database. METHODS: We retrospectively identified AML patients diagnosed from 2006 to 2015 from the Taiwan Cancer Registry Database (TCRD) and estimated the epidemiology of AML in Taiwan. The TCRD was linked to National Health Insurance Research Database (NHIRD) to collect the treatment patterns and health care utilization. Patients diagnosed with AML from 2011 to 2015 were further identified to analyze treatment patterns, healthcare utilization and costs. RESULTS: The crude annual incidence of AML increased from 2.78 to 3.21 cases per 100,000 individuals from 2006 to 2015. However, the age-standardized rate (ASRs) of AML slightly declined from 2.47 to 2.41 cases per 100,000 individuals in the same period. Among 2,179 AML patients who received induction therapy (median age: 56 years), most of them (n = 1744; 80.04%) received standard-dose cytarabine (SDAC) regimen. The remaining 162 patients received high dose cytarabine (HDAC) and 273 patients received non-standard dose cytarabine (N-SDAC) regimen as the induction therapy. The median medical costs in our study for patients treated with chemotherapy alone was $42,271 for HDAC, $36,199 for SDAC and $36,250 for N-SDAC. For those who received hematopoietic stem cell transplantation (HSCT) after induction therapy, their median medical costs were $78,876 for HDAC, $78,593 for SDAC and $79,776 for N-SDAC. CONCLUSIONS: This study is the first population-based study conducted in Asia to provide updated and comprehensive information on epidemiology, treatment patterns and healthcare resource utilization and costs of AML.

Busulfan-containing conditioning regimens in allogeneic hematopoietic stem cell transplantation for acute lymphoblastic leukemia: A Taiwan observational study.

BACKGROUND: Allogeneic stem cell transplantation (allo-HSCT) is the ultimate cure for acute lymphoblastic leukemia (ALL). AIM: This study was performed to compare the outcomes of ALL patients receiving busulfan (Bu) with cyclophosphamide (Cy)-based or total body irradiation (TBI)-based regimen in a Chinese population. METHODS: We enrolled 224 adult patients with ALL who received allo-HSCT at National Taiwan University Hospital between 1997 and 2016. RESULTS: The median age at transplantation was 33 years. Before allo-HSCT, 75.9% of patients attained first or late complete remission. A total of 141 patients (62.9%) received Bu/Cy-based conditioning, either myeloablative (MA) or reduced-intensity stem cell transplantation (RIST), and 83 patients received a TBI-based regimen (MA-TBI). Patients receiving the MA-Bu regimen had longer relapse-free survival (RFS) than those receiving the MA-TBI regimen (median, 24.1 vs. 6.7 months, p = .044). There was no difference in overall survival (OS, MA-Bu vs. MA-TBI vs. RIST-Bu: 39.4 vs. 28.2 vs. 13.1 months, p = .276), treatment-related mortality (TRM), or incidences of grade 3-4 acute graft-versus-host disease (GvHD). Among patients receiving identical GvHD prophylactic regimens, there was no difference between MA-Bu and MA-TBI groups regarding the incidence of grade 3-4 acute GvHD, grade 2-4, and all-grade chronic GvHD. In subgroup analysis, patients receiving oral busulfan had comparable RFS and OS to the intravenous busulfan group (p = .436 and p = .236, respectively), but a higher TRM (25% vs. 9.8%, p = .016). In the multivariable analysis, disease status before allo-HSCT was the only risk factor impacting RFS and OS. CONCLUSION: In summary, patients receiving Bu/Cy-based or TBI-based regimens as conditioning had similar results in terms of OS, TRM, and acute GvHD, whereas the use of myeloablative Bu/Cy resulted in a better RFS. A Bu-based regimen could be an alternative conditioning choice for patients who are ineligible to receive TBI. Prospective and randomized controlled trials are warranted to validate the long-term outcomes.

Tyrosine Kinase Inhibitors and Vascular Adverse Events in Patients with Chronic Myeloid Leukemia: A Population-Based, Propensity Score-Matched Cohort Study.

BACKGROUND: Tyrosine kinase inhibitors (TKIs) have shown long-term survival benefits in patients with chronic myeloid leukemia (CML). Nevertheless, significant concern has been raised regarding long-term TKI-associated vascular adverse events (VAEs). The objective of this retrospective cohort study was to investigate the incidence of VAEs in Taiwanese patients with CML treated with different TKIs (imatinib, nilotinib, and dasatinib) as well as potential risk factors. MATERIALS AND METHODS: We conducted a retrospective cohort study using the Taiwan Cancer Registry Database and National Health Insurance Research Database. Adult patients diagnosed with CML from 2008 to 2016 were identified and categorized into three groups according to their first-line TKI treatment (imatinib, nilotinib, and dasatinib). Propensity score matching was performed to control for potential confounders. Cox regressions were used to estimate the hazard ratio (HR) of VAEs in different TKI groups. RESULTS: In total, 1,111 patients with CML were included in our study. We found that the risk of VAEs in nilotinib users was significantly higher than that in imatinib users, with an HR of 3.13 (95% confidence interval (CI), 1.30-7.51), whereas dasatinib users also showed a nonsignificant trend for developing VAEs, with an HR of 1.71 (95% CI, 0.71-4.26). In multivariable logistic regression analysis, only nilotinib usage, older age, and history of cerebrovascular diseases were identified as significant risk factors. The annual incidence rate of VAEs was highest within the first year after the initiation of TKIs. CONCLUSION: These findings can support clinicians in making treatment decisions and monitoring VAEs in patients with CML in Taiwan. IMPLICATIONS FOR PRACTICE: This study found that patients with chronic myeloid leukemia (CML) treated with nilotinib and dasatinib may be exposed to a higher risk of developing vascular adverse events (VAEs) compared with those treated with imatinib. Thus, this study suggests that patients with CML who are older or have a history of cerebrovascular diseases should be under close monitoring of VAEs, particularly within the first year after the initiation of tyrosine kinase inhibitors.

Real-World Outcomes of Patients with Acute Myeloid Leukemia in Taiwan: A Nationwide Population-Based Study, 2011-2015.

BACKGROUND: Acute myeloid leukemia (AML) is a hematological malignancy originating from myeloid precursor cells, with different cytogenetic abnormalities, genetic mutations and diverse clinical prognoses. We investigated the clinical characteristics, treatment patterns, and outcomes of adult AML patients in Taiwan. MATERIALS AND METHODS: We retrospectively included 3851 patients with AML in the Taiwan Cancer Registry Database from 2011 to 2015. We excluded patients younger than 20 years, with acute promyelocytic leukemia, and with no pathological confirmation. RESULTS: Among the 3292 patients included, 2179 received induction chemotherapy and 1113 did not, because of older age and higher Charlson comorbidity index (CCI) score. Among the 2179 treated patients, 162 received high-dose cytarabine-based chemotherapy, 1535 received standard-dose cytarabine with anthracyclines, 209 received low-dose cytarabine-based chemotherapy, and 273 received chemotherapy without cytarabine. Patients in the low-dose cytarabine group had the oldest age and highest CCI scores compared with the other groups. In the analysis of overall survival (OS), the median OS of the overall study population was 6.27 months. Treated patients with AML had a longer OS than untreated ones (12.43 months treated vs. 2.03 months not treated; P < .0001). In the multivariate analyses of the treated patients with AML, several factors indicated better prognosis, including receiving standard-dose or high-dose cytarabine, female sex, younger age, lower CCI score, treatment at a medical center, favorable cytogenetic abnormalities, and allogeneic hematopoietic stem cell transplantation. CONCLUSION: Our study was a population-based study that illustrates the real-world outcomes of adult patients with AML in Taiwan.

Epidemiology, treatment patterns and survival of chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL) in Taiwan, 2006-2015.

AIM/OBJECTIVE: Chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL) is one of the most frequent types of leukaemia/lymphoma in adults in Western countries. However, there are few studies regarding its epidemiology and treatment patterns in Asian countries. METHODS: To investigate CLL/SLL in Asian populations, we identified CLL/SLL patients diagnosed during 2006 to 2015 from the Taiwan Cancer Registry Database and estimated the incidence. Further, patients diagnosed during 2008 to 2015 were included for the analysis of treatment patterns and survivals. Treatments for CLL/SLL were retrieved from the Taiwan's National Health Insurance Research Database and survival data from the National Death Registry. RESULTS: In total, 1497 patients who were older than 20 years and had newly diagnosed CLL/SLL during 2006-2015 were identified. The age-standardized incidence rates of CLL/SLL (0.36 per 100 000 persons in 2006, and 0.54 in 2015) increased during the 10-year period. The sex ratio was ranged from 1.21 to 2.63 with male predominant during 2006 and 2015. For the analysis of treatment patterns (n = 1236), 72.8% patients received chemotherapies. The median duration between the diagnosis and start of treatments was 27 days, and monotherapy of chlorambucil, bendamustine or cyclophosphamide was the most common regimen in initial treatments. The median follow-up duration for the patients receiving therapies was 29.6 months, and 45.0% patients experienced relapse or refractory. In patients with relapse/refractory CLL/SLL, 34.1% received rituximab-containing chemotherapies. Three hundred and ninety-nine (32.3%) patients received intensive treatments, and 175 (43.9%) of them received rituximab-containing chemotherapies. The 5-year overall survival (OS) rate was 61%, and age was an important prognostic factor for CLL/SLL patients. CONCLUSIONS: This study is the first population-based study in Asia and provides comprehensive evidence of epidemiology, treatment patterns and survivals of CLL/SLL in an Asian population.

Antiviral prophylaxis for hepatitis B carriers improves the prognosis of diffuse large B-cell lymphoma in Taiwan - a population-based study.

The prevention of hepatitis B virus (HBV) reactivation during rituximab treatment for diffuse large B-cell lymphoma (DLBCL) is important in the HBV-endemic area. This population-based study examines the impact of antiviral prophylaxis for DLBCL patients with HBV infections. We identified 3702 adult patients with newly diagnosed DLBCL between 2011 and 2015 receiving R-CHOP, R-CVP, CHOP or CVP from the Taiwan Cancer Registry. We further stratified them into three groups: HBsAg-negative patients (HBV-negative, N = 2921), HBV carriers who received antiviral prophylaxis (HBV + Px, N = 711), and HBV carriers who did not receive antiviral prophylaxis (HBV + No Px, N = 70). HBV + Px patients were the youngest, and 69·4% received entecavir for antiviral prophylaxis. The median overall survival (mOS) of HBV-negative and HBV + Px patients was similar (74·23 months and not reached, respectively). However, the mOS of HBV + No Px patients was only 35·61 months (P = 0·0028 compared with HBV + Px patients), indicating that antiviral prophylaxis improves OS in HBsAg-positive DLBCL patients. The multivariate analysis showed that the HBV status and antiviral prophylaxis was an independent prognostic factor. In conclusion, our population-based study illustrates the importance of antiviral prophylaxis in HBsAg-positive DLBCL patients. Under antiviral prophylaxis, the survival of DLBCL patients with HBV infections was comparable to that of HBV-negative patients.

Frontline treatments in extremely elderly patients with diffuse large B-cell lymphoma: a population-based study in Taiwan, 2010-2015.

BACKGROUND: The standard frontline therapy for patients with diffuse large B cell lymphoma (DLBCL) is R-CHOP. However, patients older than 80 years are excluded from clinical trials. The importance of rituximab and anthracycline remains unknown in extremely elderly DLBCL patients. Here, we incorporated data from the Taiwan Cancer Registry Database (TCRD), National Health Insurance Research Database (NHIRD), and National Death Registry to evaluate the clinical benefits of rituximab and anthracycline in elderly patients. From the TCRD and NHIRD, we included DLBCL patients aged older than 60 years who received R-CHOP, R-CVP, CHOP, or CVP between 2010 and 2015. RESULTS: Of the 3228 eligible patients, 2559 were between 60 and 79 years (the 60-79 group), and 669 were older than 80 years (the 80+ group). The proportions of patients in the different Ann Arbor stages and the practice settings were similar in both groups. The male-to-female ratio and the Charlson comorbidity index (CCI) scores in the 80+ group were higher than those in the 60-79 group. Patients in the 60-79 group received R-CHOP more frequently than those in the 80+ group. In the 60-79 group, the median age of the patients receiving R-CVP or CVP was older than those receiving R-CHOP or CHOP. In the analysis of overall survival (OS) and time to treatment failure (TTF), R-CHOP, female sex, younger age, lower Ann Arbor stage, lower CCI score, and care at a medical center predicted a favorable prognosis in the 60-79 group. However, only R-CHOP, younger age, and lower Ann Arbor stage remained independent favorable prognostic factors in the 80+ group. CONCLUSIONS: Our population-based study demonstrated the clinical benefits of rituximab and anthracycline in extremely elderly Asian patients with DLBCL.

Long non-coding RNA HOXB-AS3 promotes myeloid cell proliferation and its higher expression is an adverse prognostic marker in patients with acute myeloid leukemia and myelodysplastic syndrome.

BACKGROUND: Long non-coding RNAs (lncRNAs) represent the majority of cellular transcripts and play pivotal roles in hematopoiesis. However, their clinical relevance in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) remains largely unknown. Here, we investigated the functions of HOXB-AS3, a lncRNA located at human HOXB cluster, in the myeloid cells, and analyzed the prognostic significances in patients with AML and MDS. METHODS: shRNAs were used to downregulate HOXB-AS3 in the cell lines and the effect was evaluated by quantitative polymerase chain reaction. The proliferation of the cell lines was illustrated by proliferation and BrdU flow assays. Further, we retrospectively analyzed the HOXB-AS3 expression in 193 patients with AML and 157 with MDS by microarray analysis, and evaluated its clinical importance. RESULTS: Downregulation of HOXB-AS3 suppressed cell proliferation. Mechanistically, HOXB-AS3 potentiated the expressions of several key factors in cell cycle progression and DNA replication without affecting the expressions of HOX genes. In AML, patients with higher HOXB-AS3 expression had shorter survival than those with lower HOXB-AS3 expression (median overall survival (OS), 17.7 months versus not reached, P <  0.0001; median relapse-free survival, 12.9 months versus not reached, P = 0.0070). In MDS, patients with higher HOXB-AS3 expression also had adverse prognosis compared with those with lower HOXB-AS3 expression (median OS, 14.6 months versus 42.4 months, P = 0.0018). The prognostic significance of HOXB-AS3 expression was validated in the TCGA AML cohort and another MDS cohort from our institute. The subgroup analyses in MDS patients showed that higher HOXB-AS3 expressions could predict poor prognosis only in lower-risk (median OS, 29.2 months versus 77.3 months, P = 0.0194), but not higher-risk group. CONCLUSIONS: This study uncovers a promoting role of HOXB-AS3 in myeloid malignancies and identifies the prognostic value of HOXB-AS3 expression in AML and MDS patients, particularly in the lower-risk group.

Women with Diffuse Large B Cell Lymphoma Benefit More from Rituximab-Containing Chemotherapy.

BACKGROUND: Diffuse large B cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma. The treatment response and overall survival (OS) improved after incorporating rituximab with chemotherapies. Yet, available evidence as to whether women and men may benefit similarly from rituximab have not been adequately addressed, particularly in the real-world setting. The objective of this study was to examine sex differences in the clinical outcomes of rituximab in DLBCL patients using the Taiwan Cancer Registry Database and National Health Insurance Research Database. MATERIALS AND METHODS: All DLBCL patients aged 20 years and older during 2009-2013 were identified (n = 4490; women = 2048). Cox proportional hazard models were used to compare the results. RESULTS: The baseline characteristics were similar between women and men with DLBCL, except that women had lower Charlson comorbidity index (CCI), and that fewer women underwent R-CHOP. In the survival analysis, women had better OS and longer time to treatment failure. The multivariate analysis of OS showed that the female sex remained to be an independent favorable prognostic factor regardless of Ann Arbor stages, age, treatments, CCI, and practice settings. In the subgroup analysis, the female advantage was only significant in the patients receiving rituximab-CHOP chemotherapy instead of in those receiving other rituximab-containing or non-rituximab therapies. This advantage diminished when rituximab dose was higher. CONCLUSION: From our population-based study, women demonstrated more survival benefits from the use of rituximab-containing induction chemotherapies for DLBCL.

Subtype-specific epidemiology of lymphoid malignancies in Taiwan compared to Japan and the United States, 2002-2012.

BACKGROUND: There are many unrevealed parts regarding lymphoma etiology. Previous studies suggested differences in lymphoma epidemiology among countries existed; however, some were one-center studies that were not enough to represent the whole population. OBJECTIVE: To provide epidemiological information on lymphoma within Taiwanese and to compare the data with that in Japan and the United States. METHODS: We used Taiwan Cancer Registry Database as our data source. Patients with lymphoma were identified through the ICD-O-3 codes and those with non-Hodgkin lymphoma (NHL) were categorized into three major types and 13 subtypes according to 2008 WHO classification. Incidence of lymphoma was adjusted according to the 2000 world standard population. RESULTS: During 2002-2012, 21 929 cases were diagnosed with four major types of lymphoma in Taiwan. Aggressive B-cell lymphoma (52.21%, N = 11 450) was the most common type of NHL. Median age at diagnosis of aggressive B-cell lymphoma was the eldest (63.0-65.0 years). Male excess in T/NK-cell lymphoma was the most obvious (sex ratio: 1.39-2.07). The incidence of NK/T-cell lymphoma, nasal type, was higher (male: 0.16-0.34 per 100 000, female: 0.06-0.16 per 100 000) in Taiwan than that in the United States and Japan. CONCLUSION: This is the first population-based study in Taiwan to investigate subtype-specific epidemiology of lymphoma. The incidence rates of lymphoma in Taiwan are mostly lower than those in the United States and higher or comparable to those in Japan except for NK/T-cell lymphoma, nasal type, whose age-adjusted incidence in Taiwan is the highest.

Clinically validated machine learning algorithm for detecting residual diseases with multicolor flow cytometry analysis in acute myeloid leukemia and myelodysplastic syndrome.

BACKGROUND: Multicolor flow cytometry (MFC) analysis is widely used to identify minimal residual disease (MRD) after treatment for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). However, current manual interpretation suffers from drawbacks of time consuming and interpreter idiosyncrasy. Artificial intelligence (AI), with the expertise in assisting repetitive or complex analysis, represents a potential solution for these drawbacks. METHODS: From 2009 to 2016, 5333 MFC data from 1742 AML or MDS patients were collected. The 287 MFC data at post-induction were selected as the outcome set for clinical outcome validation. The rest were 4:1 randomized into the training set (n = 4039) and the validation set (n = 1007). AI algorithm learned a multi-dimensional MFC phenotype from the training set and input it to support vector machine (SVM) classifier after Gaussian mixture model (GMM) modeling, and the performance was evaluated in The validation set. FINDINGS: Promising accuracies (84·6% to 92·4%) and AUCs (0·921-0·950) were achieved by the developed algorithms. Interestingly, the algorithm from even one testing tube achieved similar performance. The clinical significance was validated in the outcome set, and normal MFC interpreted by the AI predicted better progression-free survival (10·9 vs 4·9 months, p < 0·0001) and overall survival (13·6 vs 6·5 months, p < 0·0001) for AML. INTERPRETATION: Through large-scaled clinical validation, we showed that AI algorithms can produce efficient and clinically-relevant MFC analysis. This approach also possesses a great advantage of the ability to integrate other clinical tests. FUND: This work was supported by the Ministry of Science and Technology (107-2634-F-007-006 and 103-2314-B-002-185-MY2) of Taiwan.

Rituximab maintenance improves overall survival in follicular lymphoma: A retrospective nationwide real-world analysis from Taiwan Cancer Registry Database.

Follicular lymphoma (FL) is the most frequent indolent lymphoma in Western countries, but it is less frequent in Asia. Several trials have demonstrated the progression-free benefit of rituximab maintenance for FL patients in Western countries. However, the overall survival (OS) benefits and effectiveness of rituximab maintenance in Asian FL patients remain uncertain. We utilized the Taiwan Cancer Registry Database and the National Health Insurance Research Database to investigate the roles of rituximab maintenance for newly diagnosed FL patients in Taiwan. Among 836 patients with newly diagnosed FL during 2009-2012, we enrolled patients with stage II-IV diseases receiving 4-8 cycles of rituximab-containing induction chemotherapies (R-induction). We excluded those who died or received additional chemotherapy within 180 days after R-induction. Among the 396 enrolled patients, 260 underwent rituximab maintenance (R-maintenance group), and 136 served as the observation group. The R-maintenance group received less anthracycline and fewer cycles of R-induction than the observation group, but they exhibited a significantly better OS both in the univariate and multivariate analyses [hazard ratio, 0.42; 95% confidence interval, 0.19-0.91] after adjusting for age, sex, and Ann Arbor stages. Meanwhile, we also found more patients required further therapies in the first 6 months after the cease of rituximab maintenance. In the subgroup analysis, patients older than 60 years or with stage IV diseases benefited more from rituximab maintenance. Conclusively, our nationwide study is the first one to demonstrate the OS benefit of rituximab maintenance after induction therapies in newly diagnosed FL patients from Asian populations.

Cervical Papanicolaou Smears in Hematopoietic Stem Cell Transplant Recipients: High Prevalence of Therapy-Related Atypia during the Acute Phase.

Hematopoietic stem cell transplant (HSCT) recipients have a higher risk of cervical cancer. Papanicolaou (Pap) smear is the standard tool for screening cervical cancer, but there is limited research about the cervical cytology in HSCT recipients. Here, we retrospectively included adult female patients who underwent allogeneic or autologous HSCT at National Taiwan University Hospital during 2009 to 2015 and reviewed their Pap smears before and after HSCT. There were 248 allogeneic and 131 autologous HSCT recipients in our study. In allogeneic HSCT recipients, 38.7% (96 of 248) had pre-HSCT Pap smears and 17.1% (44 of 248) had post-HSCT Pap smears. In the autologous HSCT recipients, 35.1% (46 of 131) had pre-HSCT Pap smears and 13.7% (18 of 131) had post-HSCT Pap smears. Compared with allogeneic HSCT recipients without post-HSCT Pap smears, more recipients with post-HSCT Pap smears received bone marrow-derived stem cells (18.2% versus 4.9% respectively; P = .0077) and had longer overall survival (median overall survival, not reached versus 22.1 months; P < .0001). The abnormal rates of post-HSCT Pap smear were 13% (6 of 44) and 11% (2 of 18) in allogeneic and autologous recipients respectively, higher than in the general Taiwanese population (1.22%). Infections were rare in post-HSCT Pap smears. Of note, 11% (5 of 44) of post-HSCT Pap smears from allogeneic recipients showed therapy-related atypia, manifesting as enlarged hyperchromatic nuclei, vacuolated cytoplasm, and occasional tadpole-like cells. These atypical cytological features mimic precancerous lesions, but cervical biopsies and human papilloma virus tests were negative. The atypical cytological features resolved spontaneously in the subsequent follow-up Pap smears. On average, Pap smears with therapy-related atypia were sampled at day +77, significantly earlier than those without therapy-related atypia (P = .016). Therapy-related atypia was more frequent in post-HSCT Pap smears sampled within 100 days after HSCT (before day +100, 4 of 5, 80%, versus after day +100, 1 of 39, 2.56%; P = .0002). The strong temporal relationship suggests these atypical cytological changes resulted from conditioning regimen, most likely busulfan-containing chemotherapy. No therapy-related atypia were observed after total body irradiation or nonbusulfan-containing chemotherapy. In conclusion, therapy-related atypia was common in post-HSCT Pap smears sampled within 100 days after HSCT. Clinical information is critical for correct cytological diagnosis.