Treatment of thalassaemia: a review of the new approaches on transfusion safety and the novel therapeutics

Lifetime red cell concentrate (RCC) transfusions still account for significant iron overload‐related morbidity and mortality despite chelation therapy in thalassaemia. The cumulative risk of transfusion‐transmitted infections is substantial for thalassaemia patients. Pathogen reduction technologies for RCC may imply a proactive approach against new/re‐emerging pathogens and may be an ultimate safeguard for transfusion safety in the developing countries. Red cell alloimmunization may become a significant clinical challenge in thalassaemia. The availability of high‐throughput molecular blood group antigen typing in the donors may allow perfect match transfusion, beyond ABO‐D and CEK antigen‐matched transfusions. Allogeneic stem cell transplantation (A‐SCT) is the only available curative therapy in thalassaemia, but carries a substantial risk of serious adverse events and mortality. Gene addition therapy for correction of the α‐globin chain imbalance overcomes the problems of donor availability and immunological complications of A‐SCT. Gene editing by either gene disruption or correction emerged as a potential alternative to gene addition therapy in beta‐thalassaemia. A new era of novel therapeutics targeting α/β imbalance, ineffective erythropoiesis or iron dysregulation is unfolding in thalassaemia management, and a number of those now have agents in preclinical and clinical development. Hydroxyurea (HU) may improve globin chain imbalance and be beneficial for reducing or omitting transfusion requirement. Ruxolitinib has allowed steady decrease in spleen volume that may serve for avoiding splenectomy in beta‐thalassaemia. Luspatercept may restore normal erythroid differentiation and improve anaemia. Hepcidin mimetics or TMPRSS6 inhibitors may modulate ineffective erythropoiesis by iron restriction and improve anaemia and organ iron loading.     

Differentiating autoimmune pancreatitis from pancreatic ductal adenocarcinoma with CT radiomics features

PurposeThe purpose of this study was to determine whether computed tomography (CT)-based machine learning of radiomics features could help distinguish autoimmune pancreatitis (AIP) from pancreatic ductal adenocarcinoma (PDAC).Materials and MethodsEighty-nine patients with AIP (65 men, 24 women; mean age, 59.7 ± 13.9 [SD] years; range: 21–83 years) and 93 patients with PDAC (68 men, 25 women; mean age, 60.1 ± 12.3 [SD] years; range: 36–86 years) were retrospectively included. All patients had dedicated dual-phase pancreatic protocol CT between 2004 and 2018. Thin-slice images (0.75/0.5 mm thickness/increment) were compared with thick-slices images (3 or 5 mm thickness/increment). Pancreatic regions involved by PDAC or AIP (areas of enlargement, altered enhancement, effacement of pancreatic duct) as well as uninvolved parenchyma were segmented as three-dimensional volumes. Four hundred and thirty-one radiomics features were extracted and a random forest was used to distinguish AIP from PDAC. CT data of 60 AIP and 60 PDAC patients were used for training and those of 29 AIP and 33 PDAC independent patients were used for testing.ResultsThe pancreas was diffusely involved in 37 (37/89; 41.6%) patients with AIP and not diffusely in 52 (52/89; 58.4%) patients. Using machine learning, 95.2% (59/62; 95% confidence interval [CI]: 89.8–100%), 83.9% (52:67; 95% CI: 74.7–93.0%) and 77.4% (48/62; 95% CI: 67.0–87.8%) of the 62 test patients were correctly classified as either having PDAC or AIP with thin-slice venous phase, thin-slice arterial phase, and thick-slice venous phase CT, respectively. Three of the 29 patients with AIP (3/29; 10.3%) were incorrectly classified as having PDAC but all 33 patients with PDAC (33/33; 100%) were correctly classified with thin-slice venous phase with 89.7% sensitivity (26/29; 95% CI: 78.6–100%) and 100% specificity (33/33; 95% CI: 93–100%) for the diagnosis of AIP, 95.2% accuracy (59/62; 95% CI: 89.8–100%) and area under the curve of 0.975 (95% CI: 0.936–1.0).ConclusionsRadiomic features help differentiate AIP from PDAC with an overall accuracy of 95.2%.     

Proteases and their inhibitors as prognostic factors for high-grade serous ovarian cancer

Ovarian carcinoma is one of the most lethal malignancies, but only very few prognostic biomarkers are known. The degradome, comprising proteases, protease non-proteolytic homologues and inhibitors, have been involved in the prognosis of many cancer types, including ovarian carcinoma. The prognostic significance of the whole degradome family has not been specifically studied in high-grade serous ovarian cancer. A targeted DNA microarray known as the CLIP-CHIP microarray was used to identify potential prognostic factors in ten high-grade serous ovarian cancer women who had early recurrence (<1.6 years) or late/no recurrence after first line surgery and chemotherapy. In women with early recurrence, we identified seven upregulated genes (TMPRSS4, MASP1/3, SPC18, PSMB1, IGFBP2, CFI – encoding Complement Factor I – and MMP9) and one down-regulated gene (ADAM-10). Using immunohistochemistry, we evaluated the prognostic effect of these 8 candidate genes in an independent cohort of 112 high-grade serous ovarian cancer women. Outcomes were progression, defined according to CA-125 criteria, and death. Multivariate Cox proportional hazard regression models were done to estimate the associations between each protein and each outcome. High ADAM-10 expression (intensity of 2–3) was associated with a lower risk of progression (adjusted hazard ratio (HR): 0.51; 95% confidence interval (CI): 0.29-0.87). High complement factor I expression (intensity 2–3) was associated with a higher risk of progression (adjusted HR: 2.30, 95% CI: 1.17–4.53) and death (adjusted HR: 3.42; 95% CI: 1.72–6.79). Overall, we identified the prognostic value of two proteases, ADAM-10 and complement factor I, for high-grade serous ovarian cancer which could have clinical significance.     

Germline gain-of-function MMP11 variant results in an aggressive form of colorectal cancer

Matrix metalloproteinase-11 (MMP11) is an enzyme with proteolytic activity against matrix and nonmatrix proteins. Although most MMPs are secreted as inactive proenzymes and are later activated extracellularly, MMP11 is activated intracellularly by furin within the constitutive secretory pathway. It is a key factor in physiological tissue remodeling and its alteration may play an important role in the progression of epithelial malignancies and other diseases. TCGA colon and colorectal adenocarcinoma data showed that upregulation of MMP11 expression correlates with tumorigenesis and malignancy. Here, we provide evidence that a germline variant in the MMP11 gene (NM_005940: c.232C>T; p.(Pro78Ser)), identified by whole exome sequencing, can increase the tumorigenic properties of colorectal cancer (CRC) cells. P78S is located in the prodomain region, which is responsible for blocking MMP11's protease activity. This variant was detected in the proband and all the cancer-affected family members analyzed, while it was not detected in healthy relatives. In silico analyses predict that P78S could have an impact on the activation of the enzyme. Furthermore, our in vitro analyses show that the expression of P78S in HCT116 cells increases tumor cell invasion and proliferation. In summary, our results show that this variant could modify the structure of the MMP11 prodomain, producing a premature or uncontrolled activation of the enzyme that may contribute to an early CRC onset in these patients. The study of this gene in other CRC cases will provide further information about its role in CRC development, which might improve patient treatment in the future.     

Improving Prenatal Diagnosis of Coarctation of the Aorta

Background

The purpose of the study was to evaluate the association between fetal echocardiographic measurements and the need for intervention (primary coarctation repair, staged coarctation repair, or catheter intervention) in prenatally diagnosed coarctation of the aorta.

A review of neurocognitive functioning of children with sex chromosome trisomies: Identifying targets for early intervention

Sex chromosome trisomies (SCT) are among the most common chromosomal duplications in humans. Due to recent technological advances in non-invasive screening, SCT can already be detected during pregnancy. This calls for more knowledge about the development of (young) children with SCT. This review focused on neurocognitive functioning of children with SCT between 0 and 18 years, on domains of global intellectual functioning, language, executive functioning, and social cognition, in order to identify targets that could benefit from early treatment. Online databases were used to identify peer-reviewed scientific articles using specific search terms. In total 18 studies were included. When applicable, effect sizes were calculated to indicate clinical significance. Results of the reviewed studies show that although traditionally, the focus has been on language and intelligence (IQ) in this population, recent studies suggest that executive functioning and social cognition may also be significantly affected already in childhood. These findings suggest that neuropsychological screening of children diagnosed with SCT should be extended, to also include executive functioning and social cognition. Knowledge about these neurocognitive risks is important to improve clinical care and help identify targets for early support and intervention programs to accommodate for the needs of individuals with SCT.     

富亮氨酸胶质瘤失活1蛋白抗体阳性边缘性脑炎 临床分析及文献复习

目的：总结富亮氨酸胶质瘤失活1蛋白（LGI1）抗体阳性边缘性脑炎的临床和影像特点及诊疗预后。 方法：报道我院1例LGI1抗体阳性相关边缘性脑炎并文献复习。结果：患者女性，60岁，表现为渐进性加重 的记忆力减退、癫痫发作（全身强直阵挛发作，面-臂肌张力障碍发作）、低钠血症和轻度精神行为异常。颅 脑MRI-T2/Flair序列提示双侧颞叶（左侧为甚）内侧、海马异常高信号。脑脊液抗LGI1抗体阳性（++）。经激 素治疗症状有所改善。检索既往报道LGI1抗体阳性边缘性脑炎患者237例，多数呈急性、亚急性起病，最 常见是记忆障碍、癫痫（含面-臂肌张力障碍发作）和低钠血症，头颅MRI（特别是MRI-T2/Flair序列）显示单 侧或者双侧海马区、颞叶异常多见，早期免疫治疗预后良好。结论：LGI1抗体阳性相关边缘性脑炎有其特 有的临床特点，免疫治疗可明显改善患者预后。     

Pangenomic Classification of Pituitary Neuroendocrine Tumors

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Building and Exploitation of Learning Curves to Train Radiographer Students in X-Ray CT Image Postprocessing

IntroductionThis study aims to construct learning curves related to the realization of standardized postprocessing by radiographer students and to discuss their exploitation and interest.Materials and MethodsThis study was carried out in 21 French students in their 3rd year of training. Two postprocessing protocols in CT (#1 traumatic shoulder; #2 petrous bone) were repeated 15 times by each student. Each achievement was timed to obtain overall learning curves. The realization accuracy was also assessed for each student at each repetition.ResultsThe learning rates for the two protocols are 63% and 56%, respectively. The number of repetitions to reach the reference time for each protocol is 11 and 12, respectively. In both protocols, the standard deviations are significantly reduced and stabilized during repetitions. The mean accuracy progresses more quickly in protocol #1.DiscussionThe measured learning rates reflect a rapid learning process for each protocol. The analysis of the standard deviations shows that students have reached a homogeneous level. The average times and accuracies measured during the last repetitions show that the group has reached a high level of performance. Building learning curves helps students measure their progress and motivates them.ConclusionObtaining learning curves allows trainers/supervisors to qualify the learning difficulty of a task while motivating students/radiographers. The use of learning curves is inline with the competency-based training paradigm.