CT-based radiomics model with machine learning for predicting primary treatment failure in diffuse large B-cell Lymphoma

Biomarkers which can identify Diffuse Large B-Cell Lymphoma (DLBCL) likely to be refractory to first-line therapy are essential for selecting this population prior to therapy initiation to offer alternate therapeutic options that can improve prognosis. We tested the ability of a CT-based radiomics approach with machine learning to predict Primary Treatment Failure (PTF)-DLBCL from initial imaging evaluation. Twenty-six refractory patients were matched to 26 non-refractory patients, yielding 180 lymph nodes for analysis. Manual 3D delineation of the total node volume was performed by two independent readers to test the reproducibility. Then, 1218 hand-crafted radiomic features were extracted. The Random Forests machine learning approach was used as a classifier for constructing the prediction models. Seventy percent of the nodes were randomly assigned to a training set and the remaining 30% were assigned to an independent test set. The final model was tested on the dataset from the 2 readers, showing a mean accuracy, sensitivity and specificity of 73%, 62% and 82%, respectively, for distinguishing between refractory and non-refractory patients. The area under the receiver operating characteristic curve (AUC) was 0.83 and 0.79 for the two readers. We conclude that machine learning CT-based radiomics analysis is able to identify a priori PTF-DLBCL with a good accuracy.     

Development of new Malt1 inhibitors and probes

Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (Malt1) is a promising therapeutic target for the treatment of activated B cell-like diffuse large B cell lymphoma (ABC-DLBCL). Several research groups have reported on the development of Malt1 inhibitors and activity-based probes for in vitro and in situ monitoring and modulating Malt1 activity. In this paper, we report on two activity-based Malt1 probes (6 and 7) and a focused library of 19 new Malt1 inhibitors. Our peptide-based probe 6 labels Malt1 in an activity-based manner. In contrast, probe 7, derived from the known covalent inhibitor MI-2, labels both wild type and catalytically inactive Cys to Ala mutant Malt1, suggesting that MI-2 inhibits Malt1 by reacting with a nucleophilic residue other than the active site cysteine. Furthermore, two of our inhibitors (9, apparent IC₅₀ 3.0 μM, and 13, apparent IC₅₀ 2.1 μM) show good inhibitory activity against Malt1 and outperform MI-2 (apparent IC₅₀ 7.8 μM) in our competitive activity-based protein profiling assay.     

Potentiating effect of heparin in the activation of procollagenase by a low-Mr angiogenesis factor

A low-Mr freely dialysable endothelial cell-stimulating angiogenesis factor (ESAF) from conditioned medium of a mouse lymphoma cell line has previously been shown to activate latent skin fibroblast procollagenase. Activation comparable with the maximum that can be achieved with trypsin is obtained with chemically undetectable amounts of the factor. We now show that when even smaller amounts of ESAF are used heparin is able to potentiate its action in this system. The relationship between this activity and the mechanism of angiogenesis, which is itself potentiated by heparin, is discussed.     

Evaluation of disparities in maintaining healthy lifestyle behaviors among female cancer survivors by race/ethnicity and US nativity

BackgroundThere are well-known racial/ethnic disparities in maintaining healthy lifestyle behaviors throughout cancer survivorship among US-born women. Less is known about these associations among women born outside the US, as these women may experience disparities in survivorship care due to the lack of access to culturally appropriate health services. We evaluated disparities in the associations between race/ethnicity and US nativity and the likelihood of meeting recommendations for maintaining a healthy lifestyle during cancer survivorship.Methods2044 female cancer survivors contributed data from the National Health and Nutrition Examination Survey (NHANES) (1999–2018). Adjusted odds ratios (aORs) and 95 % confidence intervals (CIs) were calculated with multivariable logistic regression models to measure the association between independent variables (race/ethnicity, US nativity, length of time in the US) and outcomes (obesity, meeting weekly physical activity (PA) recommendations, smoking history, alcoholic drinks/day) overall and by comorbidity.ResultsMost survivors were breast cancer survivors (27.6 %), non-Hispanic white (64.2 %), and US native (84.5 %). Compared to US native survivors, foreign-born survivors were less likely (aOR, 0.30, 95 % CI, 0.10–0.87) to not meet PA recommendations, while foreign-born survivors living in the US ≥ 15 years were 2.30 times more likely (95 % CI, 1.12–4.73) to not meet PA recommendations. Having at least one comorbidity modified (p-interaction< 0.05) the relationships between US nativity and length of time in the US.ConclusionOur findings provide new evidence for disparities in maintaining healthy lifestyle behaviors among female cancer survivors and can help inform lifestyle interventions for female cancer survivors from different racial/ethnic backgrounds.     

Expression of the MDR1 and MRP Genes in Patients with Lymphoma with Primary Bone Marrow Involvement

Expression of MDR1 and MRP genes in patients with low‐grade and high‐grade non‐Hodgkin's lymphomas with primary bone marrow involvement before and after chemotherapy was investigated. The data demonstrate that overexpression of MDR1 and MRP genes in hematological malignancies elevates in patients after chemotherapy and correlates with poor clinic prognosis and more frequent recurrences of the malignancies.     

Optimization of permeability in a series of pyrrolotriazine inhibitors of IRAK4

We have developed a series of orally efficacious IRAK4 inhibitors, based on a scaffold hopping strategy and using rational structure based design. Efforts to tackle low permeability and high efflux in our previously reported pyrrolopyrimidine series (Scott et al., 2017) led to the identification of pyrrolotriazines which contained one less formal hydrogen bond donor and were intrinsically more lipophilic. Further optimisation of substituents on this pyrrolotriazine core culminated with the discovery of 30 as a promising in vivo probe to assess the potential of IRAK4 inhibition for the treatment of MyD88 mutant DLBCL in combination with a BTK inhibitor. When tested in an ABC-DLBCL model with a dual MyD88/CD79 mutation (OCI-LY10), 30 demonstrated tumour regressions in combination with ibrutinib.     

Active antitumor immunotherapy, with or without B7-mediated costimulation, increases tumor progression in an immunogenic murine T cell lymphoma model

 BW-Sp3 is a BW-5147-derived T cell lymphoma with limited immunogenicity since, despite regression of the majority of subcutaneous tumors, an important fraction of the animals will die from metastases. In the present study, the BW-Sp3 cells were transfected with genes encoding B7-1 or B7-2, known to be involved in the induction of T cell responses. The resulting transfectants exhibited a reduced tumorigenicity and did not cause mortality in the syngeneic recipients. Furthermore, immunization with the B7-1 or B7-2 transfectants resulted in an increased generation of cytotoxic T lymphocytes (CTL) that lysed both the transfectants and the wild-type BW-Sp3 cells. Since the B7 transfectants were completely rejected in syngeneic recipients and induced potent CTL recognizing the wild-type BW-Sp3 cells, these engineered cells were considered as candidates for immunotherapy. Vaccinations with the B7-1 or B7-2 transfectants could completely protect the animals from metastatic disease when subsequently challenged with wild-type BW-Sp3 cells. Furthermore, immunization with the B7 transfectants could prolong the survival time of mice that had been challenged intravenously with BW-Sp3 cells. Surprisingly, however, when these transfectants, as well as the wild-type BW-Sp3 cells, were used for vaccination of tumor-bearing animals, the presence of the subcutaneous BW-Sp3 tumors clearly interfered with the outcome of immunotherapy, resulting in increased malignancy, as reflected by a higher incidence of progressing tumors and a reduced survival rate. Possible implications for immunotherapy in humans are discussed. Received: 5 August 1997 / Accepted: 15 August 1997     

Pretargeted radioimmunotherapy using 131I-labelled bivalent hapten-bearing peptides

Summary The advantages of bivalent hapten-bearing peptides for the detection of tumours pretargeted with bispecific antibodies have been demonstrated. This technology is now considered for radioimmunotherapy and bivalent haptens designed to target¹³¹I are needed. We thus synthesised a series of tyrosine-containing peptides bearing the histamine-hemisuccinate hapten. These molecules were tested for their ability to bind simultaneously two anti-hapten antibody molecules. One of these bivalent haptens, AG3.0, with a lysyl-d-tyrosyl-lysine connecting chain, was found to have optimal binding characteristics and was thus selected for further investigations. AG3.0 was shown to efficiently deliver radioactive iodine to human colorectal tumours grafted in nude mice using an anti-carcinoembryonic antigen×anti-histamine-hemisuccinate bispecific antibody. AG3.0 was also targeted to human B lymphoma cells pretargeted with a bispecific antibody specific for membrane IgM. In this system, bivalent ligands such as F(ab′)₂ or IgG are rapidly internalised and covalently linked radioactive iodine is released from target cells as a result of intracellular catabolism. With the pretargeted iodine-labelled bivalent hapten, a fivefold increase in the intracellular activity retention time as compared to¹²⁵I-labelled F(ab′)₂ and IgG was observed. The radiolabelled hapten did not undergo any degradation after internalisation. These results have been confirmed in vivo with an anti-BCL₁ IgM idiotype bispecific antibody and¹³¹I-labelled AG3.0. These reagents injected as a single 300 μCi dose, 7 days after inoculation of 10⁴ BCL₁ lymphoma cells in BALB/c mice, cured 14/16 of the animals and the treatment was well tolerated. Comparatively, the same dose of labelled IgG cured 13/16 of the mice but three mice died of haematologic toxicity. The same dose of labelled F(ab′)₂ or Fab′ was completely inefficient.¹³¹I-labelled bivalent haptens are now used in phase I radioimmunotherapy clinical trials.     

影像学方法在淋巴瘤疗效评估中的应用

淋巴瘤通过放化疗可获得很高的治愈率。治疗过程中,疗效评估对于评价或调整治疗方案至关重要。基于病灶形态学改变的传统影像学技术如计算机断层扫描(computed tomography,CT)与磁共振成像(magnetic resonance imaging,MRI)技术在评估淋巴瘤疗效时存在一定的局限性;磁共振加权成像(diffusion-weighted imaging,DWI)结合水分子表观弥散系数(apparent diffusion coefficient,ADC)从分子水平反映疾病的病理生理状态,是一种功能成像新技术;而正电子发射断层显像/X线计算机体层成像(Positron emission tomography/computed tomography,PET/CT)将肿瘤的代谢与形态相结合,是一种新型的功能成像技术,已广泛应用于淋巴瘤患者的分期、疗效监测和预后评估中,可较其他影像学技术更准确的评估疗效;PET/MRI技术在淋巴瘤方面的临床应用研究目前尚处于初步阶段,其临床价值尚需进一步探讨。