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Several studies have compared the molecular responses between e14a2 and e13a2 BCR::ABL1 transcripts in chronic myeloid leukemia (CML) patients treated with front‐line imatinib, but there were very limited studies on nilotinib or dasatinib‐treated patients. We retrospectively analyzed the molecular responses in 1124 CML patients with the e14a2 or e13a2 transcript receiving front‐line imatinib, nilotinib or dasatinib treatment. Patients with the e14a2 transcript had higher optimal response rates than those with the e13a2 transcript at 12 months in the imatinib‐treated group, and 6 and 12 months in the nilotinib‐treated group. The optimal response rates were not significantly different between the two transcripts in the dasatinib‐treated group at landmark molecular responses. With a median follow‐up time of 48.4 months, higher cumulative incidences of BCR::ABL1 International Scale ≤1% and major molecular response were observed in patients with the e14a2 rather than the e13a2 transcript receiving front‐line imatinib or nilotinib treatment, but not in dasatinib‐treated patients. The progression‐free survival and overall survival did not differ between the two transcripts in all three treatment groups. In view of the speed and depth of molecular responses, BCR::ABL1 transcript subtypes might provide helpful information in selecting a front‐line tyrosine kinase inhibitor for individual young patients with future potential treatment‐free remission. Patients with e14a2 transcript had higher optimal response rates than e13a2 transcript at 12 months in the imatinib‐treated group, 6 and 12 months in the nilotinib‐treated group. The optimal response rates between the 2 transcripts were similar in the dasatinib‐treated group at landmark molecular responses. In view of the speed and depth of molecular responses, BCR::ABL1 transcript subtypes might provide helpful information in selecting a front‐line tyrosine kinase inhibitor for individual young patients with future potential treatment‐free remission.

Copanlisib, an intravenous pan-class I PI3K inhibitor, showed efficacy and safety as monotherapy in patients with relapsed or refractory indolent non-Hodgkin lymphoma who had received at least two therapies. The CHRONOS-3 study aimed to assess the efficacy and safety of copanlisib plus rituximab in patients with relapsed indolent non-Hodgkin lymphoma. CHRONOS-3 was a multicentre, double-blind, randomised, placebo-controlled, phase 3 study in 186 academic medical centres across Asia, Australia, Europe, New Zealand, North America, Russia, South Africa, and South America. Patients aged 18 years and older with an Eastern Cooperative Oncology Group performance status of no more than 2 and histologically confirmed CD20-positive indolent B-cell lymphoma relapsed after the last anti-CD20 monoclonal antibody-containing therapy and progression-free and treatment-free for at least 12 months, or at least 6 months for patients unwilling or unfit to receive chemotherapy, were randomly assigned (2:1) with an interactive voice-web response system via block randomisation (block size of six) to copanlisib (60 mg given as a 1-h intravenous infusion on an intermittent schedule on days 1, 8, and 15 [28-day cycle]) plus rituximab (375 mg/m2 given intravenously weekly on days 1, 8, 15, and 22 during cycle 1 and day 1 of cycles 3, 5, 7, and 9) or placebo plus rituximab, stratified on the basis of histology, progression-free and treatment-free interval, presence of bulky disease, and previous treatment with PI3K inhibitors. The primary outcome was progression-free survival in the full analysis set (all randomised patients) by masked central review. Safety was assessed in all patients who received at least one dose of any study drug. This study is registered with ClinicalTrials.gov, NCT02367040 and is ongoing. Between Aug 3, 2015, and Dec 17, 2019, 652 patients were screened for eligibility. 307 of 458 patients were randomly assigned to copanlisib plus rituximab and 151 patients were randomly assigned to placebo plus rituximab. With a median follow-up of 19·2 months (IQR 7·4–28·8) and 205 total events, copanlisib plus rituximab showed a statistically and clinically significant improvement in progression-free survival versus placebo plus rituximab; median progression-free survival 21·5 months (95% CI 17·8–33·0) versus 13·8 months (10·2–17·5; hazard ratio 0·52 [95% CI 0·39–0·69]; p<0·0001). The most common grade 3–4 adverse events were hyperglycaemia (173 [56%] of 307 patients in the copanlisib plus rituximab group vs 12 [8%] of 146 in the placebo plus rituximab group) and hypertension (122 [40%] vs 13 [9%]). Serious treatment-emergent adverse events were reported in 145 (47%) of 307 patients receiving copanlisib plus rituximab and 27 (18%) of 146 patients receiving placebo plus rituximab. One (<1%) drug-related death (pneumonitis) occurred in the copanlisib plus rituximab group and none occurred in the placebo plus rituximab group. Copanlisib plus rituximab improved progression-free survival in patients with relapsed indolent non-Hodgkin lymphoma compared with placebo plus rituximab. To our knowledge, copanlisib is the first PI3K inhibitor to be safely combined with rituximab and the first to show broad and superior efficacy in combination with rituximab in patients with relapsed indolent non-Hodgkin lymphoma. Bayer.

Image abstraction simplifies complex images, highlights specific features, and preserves different levels of structures to achieve a desired style. This paper presents a constructive and adjustable data hiding algorithm to convey various secret messages and resist modern steganalytic attacks. Our scheme produces an abstracted stego image, while synthesizing an original image during the image abstraction process. Our algorithm is flexible, applicable to two types of images: high-dynamic-range images and ordinary color images, aka low-dynamic-range images. Additionally, we introduce a novel image encryption scheme suitable for the above two types of images, which incorporates a two-dimensional logistic tent modular map and a bit-level random permutation technique, thereby further protecting the content of the stego image and the carried secret messages. Compared with the current state-of-the-art methods, our algorithm provides a 14% to 33% larger embedding rate, while lowering the distortion of the abstracted stego image. A comprehensive security analysis confirmed that our algorithm provides high security to resist statistical, differential, brute force, chosen-plaintext, and chosen key attacks.

AimsAngioimmunoblastic T cell lymphoma (AITL) is a T cell lymphoma with aberrant immune activity. It is characterised by inflammatory and immune reactions. However, the impact of regulatory T (Treg) cells on AITL remains unclear.MethodsWe retrospectively collected 46 AITL cases and performed immunohistochemical analysis of forkhead box P3 (FOXP3) expression. The number of immunostained FOXP3 cells was determined using a digital pathology system with whole-slide imaging. The average number of FOXP3+ cells per high-power field (HPF) was determined by randomly counting 20 HPFs. AITL cases were categorised into high-expression and low-expression groups based on the median count of FOXP3+ cells in all analysed samples. The relationship between FOXP3 expression and clinicopathological features was assessed.ResultsAmong the studied patients, 14 (30.4%) were females and 32 (69.6%) were males, and the median age at diagnosis was 64.1 years. The median expression of FOXP3 was 84.9 positive cells/HPF. FOXP3 expression negatively correlated with Epstein-Barr virus-encoded small RNA positivity in tumour (p=0.041). The patients with low FOXP3 expression presented with aggressive clinical behaviour, including advance-staged diseases (p=0.043), splenomegaly (p=0.008), B symptoms (p=0.019) and extranodal involvement (p=0.019). The neutrophil-to-lymphocyte ratio was higher in the patients with low FOXP3 expression, compared with those with high FOXP3 expression. Low FOXP3 expression had an adverse effect on progression-free survival (PFS, p=0.033), and increased the risk of recurrence 2.320-fold (HR 2.320 (95% CI 1.109 to 4.856); p=0.025).ConclusionsPatients with AITL with low FOXP3 expression tend to have aggressive clinical presentation and shortened PFS. These findings may help with risk stratification and determination of new treatment strategy.

The incidence of follicular lymphoma (FL) in Taiwan has not been well investigated since its inclusion as a histological subtype in the Taiwan Cancer Registry in 2008. The purpose of this study was to describe the incidence patterns of FL in Taiwan and compare the trends with those in other racial groups in the United States. We conducted an epidemiological study using population-based data from the Taiwan Cancer Registry, Ministry of Health and Welfare, and the 18 Surveillance, Epidemiology, and End Results (SEER) registries to evaluate the FL incidence from 2008 to 2017. We calculated the annual percent change (APC) to describe the trends in the incidence of FL in subpopulations defined by race and sex over time. The annual age-adjusted incidence rate of FL in Taiwan increased significantly from 0.59 per 100,000 persons in 2008 to 0.82 per 100,000 persons in 2017, with an APC of 3.2. By contrast, the incidence rate in whites in the United States during the same period decreased from 3.42 to 2.74 per 100,000 persons, with an APC of -2.1. We found no significant change for the blacks (APC, -1.5%), Hispanics (APC, -0.7%), and Asians or Pacific Islanders (APC, +0.7%). The temporal trend was similar between the males and females. The relative frequency of FL among the incident non-Hodgkin lymphoma (NHL) cases also increased significantly in Taiwan from 7.64% in 2008 to 11.11% in 2017 (APC = 3.8). The relative frequency of FL among the incident NHL cases in the whites decreased from 2008 to 2012 (APC, -3.8%) and then stabilized after 2012 (APC, -0.2%). By contrast, little change in relative frequency of FL among the incident NHL cases was observed in the blacks, Hispanics, and APIs between 2008 and 2017. We found increases in the incidence of FL and the relative frequency of FL among the incident NHL cases in both males and females in Taiwan from 2008 to 2017. The FL incidence rates were unchanged for all races and sex groups in the United States, except for the decreases in the whites.

This paper proposes a multi-hider dual-image reversible data-hiding algorithm. Generating dual stego images, the proposed algorithm provides a high embedding capacity, exhibits high image quality, offers reversibility to restore the stego images, and suggests seven levels of secret message extraction. The message embedding in our algorithm contains two phases. In Phase-1, we embed an n-ary secret message vector followed by an m-ary secret message in each pixel using two distinct secret keys when rendering a new image from the source and target images using an optimal weighted color-transfer process. This phase produces a tentative stego image which exhibits a new color appearance, different from the input source image. In Phase-2, we introduce a weighted modulus operation to embed a k-ary secret message vector into a dual-pixel constructed from the tentative stego image. The message concealment is elaborately designed so that the hidden secret messages are intact. This phase produces dual stego images which carry three distinct secret messages. Using legitimate secret keys, an authorized receiver can extract one or parts of secret messages and recover the tentative stego color-transferred image without arousing any suspicion. The experimental results and analysis confirm that our scheme can resist RS and PVD steganalytic attacks. In addition, our algorithm provides both high embedding capacity and better image quality, outperforming its counterparts. To the best of our knowledge, our scheme is the first in the relevant literature that provides multi-hider reversible data hiding, thereby offering various levels of message extraction for secure data communication.

High dynamic range (HDR) image data hiding and encryption has attracted much interest in recent years due the benefits of providing high quality realistic images and versatile applications, such as copyright protection, data integrity, and covert communication. In this paper, we propose a novel constructive and camouflaged adaptive data hiding and image encryption scheme for HDR images. Our algorithm disguises hidden messages when converting an original OpenEXR format to the RGBE encoding, which contains the Red, Green, and Blue color channels and an exponent E channel. During the conversion process, we determine an optimal base for each pixel by considering the user’s demands and the exponent E channel information to achieve adaptive message concealment. To prevent inappropriate access to the stego image, we perform the bit-level permutation and confusion using a 2D Sine Logistic modulation map with hyperchaotic behavior and a random permutation scheme with the time complexity of ON. To the best of our knowledge, our algorithm is the first in HDR data hiding literature able to predict the image distortion and satisfy a user’s request for the embedding capacity. Our algorithm offers 18% to 32% larger embedding rate than that provided by the current state-of-the-art works without degrading the quality of the stego image. Experimental results confirm that our scheme provides high security superior to the competitors.

Exogenous arginine is required for growth in some argininosuccinate synthetase (ASS)-deficient cancers. Arginine deiminase (ADI) inhibits growth in various ASS-deficient cancers by depleting arginine. The efficacy of pegylated ADI (ADI-PEG20) in relapsed/refractory/poor-risk acute myeloid leukemia (AML) was evaluated in 43 patients in a prospective, phase II trial (NCT01910012 (10/07/2013), https://clinicaltrials.gov/ct2/show/NCT01910012?term = ADI-PEG20&rank = 12 ). Despite almost all pre-treatment tumor samples showing ASS deficiency, the best response among 21 evaluable patients was complete response (CR) in 2 (9.5%) and stable disease in 7 (33.3%), yielding a disease control rate (DCR) of 42.9%. The response durations of the two patients with CR were 7.5 and 8.8 months. DCR was correlated with a median of 8 weeks of arginine depletion to ≤10 μM. Using whole transcriptome sequencing, we compared gene expression profiling of pre- and post-treatment bone marrow samples of the two responders and three non-responders. The expression levels of some markers for AML subtypes and c-MYC regulated genes were considered potential predictors of response to ADI-PEG20. These results suggest that ASS deficiency is a prerequisite but not a sufficient condition for response to ADI-PEG20 monotherapy in AML. Predictive biomarkers and mechanistic explorations will be critical for identifying appropriate patients for future AML trials of ADI-PEG20.

This paper presents an optimal weighted modulus (OWM) algorithm able to conceal secret messages in a high dynamic range image encoded via the RGBE format, consisting of the red, green, blue, and exponent channels. In contrast to current state-of-the-art schemes, which mainly employ limited and vulnerable homogeneous representations, our OWM scheme exploits four channels and an embedding weight to conceal secret messages, thereby offering more embedding capacities and undetectability against steganalytic tools. To reduce the impact on the luminance variation, we confine the maximal change incurred in the exponent channel when embedding secret messages. In addition, we propose an SEC scheme to eliminate the pixel saturation problem, even though a pixel contains values close to the boundary extreme. As a result, the stego images produced not only exhibit high quality but also comply with the RGBE encoding format, making them able to resist malicious steganalytic detection. The experimental results show that our scheme offers larger embedding rates, between 2.8074 and 5.7549 bits per pixel, and the average PSNR value for twelve tone-mapped images is over 48 dB. In addition, the HDR VDP 3.0 metric demonstrates the high fidelity of stego HDR images, where the average Q value is close to the upper bound of 10.0. Our scheme can defeat RS steganalytic attacks and resist image compatibility attacks. A comparison result confirms that our scheme outperforms six current state-of-the-art schemes.

Complete disease journey and risk factors for poor outcomes are needed to facilitate effectiveness evaluations of new therapies and clinical decision-making in B-cell Non-Hodgkin lymphoma (B-NHL), particularly in Asia where such data are lacking. This retrospective cohort study used electronic medical records from a regional medical centre in southern Taiwan to follow-up 441 patients newly diagnosed with common B-NHL subtypes: Diffuse Large B-cell Lymphoma (DLBCL), Follicular Lymphoma (FL), Chronic Lymphocytic Leukaemia/Small Lymphocytic Lymphoma (CLL/SLL), Marginal Zone Lymphoma (MZL), Mantle Cell Lymphoma (MCL), and Waldenström macroglobulinemia (WM), between 01-Jan-2008 and 31-Dec-2013, until 31-Dec-2017. Treatment pathways were modelled using a Markov approach. Stage III/IV disease at diagnosis was frequent for patients with DLBCL, FL, MCL and WM. Hepatitis B surface antigen/hepatitis C virus seropositivity was 18.6%/12.3%. Clinical responses to 1st-line treatment were observed in 76.0% (DLBCL), 87.3% (FL), 86.0% (MZL), 60.0% (MCL), and 42.9% (WM) of patients. For DLBCL, disease control was achieved by ~ 50% after 1st-line, ~ 24% after 2nd-line, ~ 17% after 3rd-line. Patients with Stage III/IV DLBCL or age > 65 years at diagnosis had lower rates of active treatment, poorer disease control and higher mortality than patients with early stage disease or age ≤ 65 years. Disease flare < 6 months after 1st-line treatment was significantly associated with mortality. Despite good clinical response rates for some sub-types, survival remains poor. New treatments are needed to improve the outcome of B-NHL.