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.     

Relationship of neutrophil gelatinase-associated lipocalin (NGAL) and procalcitonin levels with the presence and severity of the preeclampsia

Objective: The aim of the present study was to evaluate changes in maternal serum neutrophil gelatinase-associated lipocalin (NGAL) and procalcitonin (PCT) concentrations in preeclampsia.

Material and method: This case–control study consisted of 40 preeclamptic and 40 healthy singleton pregnancies matched for age and body mass index. Serum NGAL and PCT levels were compared between the groups. Diagnostic performance and clinical association of these markers were evaluated.

Results: NGAL and PCT concentrations were significantly higher in preeclamptic group (p?p?=?0.001, respectively) and their levels were correlated with the severity of the preeclampsia. There were significant positive correlation between these markers and mean arterial pressure (MAP) and spot urine protein excretion. There was negative correlation between NGAL and apgar scores and fetal birth weight. Pregnancies with higher NGAL (OR: 4.89; 95% CI: 1.81–13.21) and higher PCT (OR: 6.67; 95% CI: 2.44–18.21) concentrations had higher risk for preeclampsia.

Conclusion: NGAL and PCT may be potential biomarkers for preeclampsia. Their levels increase significantly in preeclampsia and they are related to the severity of the disease. These results are in agreement with the generalized endothelial damage and persistant inflammatory status in preeclampsia. NGAL may also be an indicator for adverse neonatal outcomes with decreased placental hypoperfusion.     

MAT2A Inhibition Blocks the Growth of MTAP-Deleted Cancer Cells by Reducing PRMT5-Dependent mRNA Splicing and Inducing DNA Damage

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Cognition of the mothers of patients with Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) has been found to be associated with cognitive impairment. However, few studies have addressed cognitive impairment among mothers of children with DMD. In the present study, the neuropsychological profiles of both carrier mothers (C-Ms) and noncarrier mothers (NC-Ms) were examined, and the findings were compared with healthy control mothers (HC-Ms). There were 90 participants, consisting of 31 C-Ms, 24 NC-Ms, and 35 HC-Ms, each of whom completed a neuropsychological test battery. C-Ms had poorer cognition performance in attention, working memory, immediate verbal memory, visuospatial skills, and executive functions than NC-Ms, and HC-Ms. This study provides evidence that there may be cognitive impairment in mothers of patients with DMD. The cognitive impairment of C-Ms has similarities to that seen in children with DMD.     

Influence of serous retinal detachment on the outcome of ranibizumab treatment in diabetic macular oedema

Purpose: The purpose of this study was to evaluate the influence of serous retinal detachment (SRD) on the outcome of intravitreal ranibizumab (IVR) therapy in diabetic macular oedema (DME).

Materials and methods: Fifty-one eyes with cystoid macular oedema (CME) and SRD (study group) and 57 eyes with only CME (control group) that received pro re nata (PRN) IVR injections during a 6-month period were retrospectively evaluated. The outcome measures included changes in the central macular thickness (CMT) and best corrected visual acuity (BCVA) and injection numbers.

Results: The mean initial CMT in the study and control groups was 467?±?101 and 440?±?89?µm, respectively. The mean BCVA in the study and control groups was 0.75?±?0.38 and 0.59?±?0.36 logarithm of minimal angle of resolution (LogMAR), respectively (p?=?0.010). The study group received a mean of 2.2?±?0.92 injections, whereas the control group received a mean of 2.54?±?0.9 injections. The decrease in CMT was greater, but not significantly greater, in the study group than in the control group.

Conclusion: The presence of SRD resulted in a less favourable visual acuity (VA) outcome with IVR. Disruption of the ellipsoid zone and abnormality of the foveal avascular zone at the baseline examination were correlated with a lower VA. Both of the pathologies occurred more frequently in the SRD group.     

The efficiency of Gd‐EOB‐DTPA‐enhanced magnetic resonance cholangiography in living donor liver transplantation: a preliminary study

The aim of this study was to evaluate utility of gadoxetic acid disodium (Gd‐EOB‐DTPA)‐enhanced magnetic resonance cholangiography (MRC) for the detection of biliary complications after living donor liver transplantation (LDLT). A total of 18 patients with suspected biliary complications underwent MRC. T2‐weighted MRC and contrast‐enhanced MRC (CE‐MRC) were used to identify the biliary complications. MRC included routine breath‐hold T2‐weighted MRC using half‐Fourier acquisition single‐shot turbo spin‐echo (HASTE) sequences and Gd‐EOB‐DTPA‐enhanced MRC T1‐weighted volumetric interpolated breath‐hold examination (VIBE) sequences. Before confirming the biliary complications, one observer reviewed the MRC images and the CE‐MRC images separately. The verification procedures and MRC findings were compared, and the sensitivity, specificity, and accuracy of both techniques were calculated for the identification of biliary complications. The observer found six of seven biliary complications using CE‐MRC. The sensitivity was 85.7% and the accuracy was 94.4%. Using MRC alone, sensitivity was 57.1% and accuracy was 55.5%. The accuracy of Gd‐EOB‐DTPA‐enhanced MRC was superior to MRC in locating biliary leaks (p < 0.05). The usage of Gd‐EOB‐DTPA‐enhanced MRC yields information that complements the MRC findings that improve the identification of biliary complications. We recommend the use of MRC in addition to Gd‐EOB‐DTPA‐enhanced MRC to increase the preoperative accuracy when assessing the biliary complications after LDLT.     

Telaprevir Experience From Turkey

Background:

In patients with chronic hepatitis C, triple drug regimens containing a protease inhibitor, peginterferon and ribavirin were found to significantly increase sustained virologic response rates compared to dual drug regimen containing pegylated interferon and ribavirin, especially in genotype 1.

Objectives:

In Turkey, telaprevir has been used since March 2013. We aimed to evaluate results of patients with chronic hepatitis C treated with telaprevir, peginterferon and ribavirin.

Patients and Methods:

We evaluated 28 patients with genotype 1 chronic hepatitis C infection treated with triple drug regimen containing telaprevir, in three medical centers in Turkey, retrospectively. Demographic data of patients, treatment indications, adverse events and outcomes were recorded.

Results:

Of 28 patients intended to treat, 25 (89.2%) patients completed the treatment. Overall, 21 (82.1%) patients had relapse and five patients were non-responder. Regarding the treatment outcomes of Telaprevir based regimen, 20/26 patients achieved sustained virological response. Pruritus, rash, dysgeusia, anorectal discomfort and anemia were main adverse effects. Blood transfusion and ribavirin dose reduction required for 7 and 11 patients, respectively. Due to several adverse effects, 10 patients were hospitalized.

Conclusions:

Although more frequent and severe adverse effects, telaprevir has been promising for patients with treatment-experienced hepatitis C.     

The Effect of Gene Mutations on Metastasis and Overall Survival in Metastatic and Nonmetastatic Colon Cancers

Objective: It is known that many genes are associated with colon cancer. We aimed to investigate the effect of gene mutations on metastasis and overall survival in metastatic and non metastatic colon cancers. Methods: A total of 50 patients with metastatic (n=25) and non metastatic (n=25) diagnosed with colon cancer between 2010 and 2018 were included in the study. APC, MUTYH, RAD50, MEN1, ATM, PALB2, NSH2, BRCA1, BRCA2, MLH1, BRIP1, TP53, PTEN, BARD1, MSH6, PMS2, NBN, and FAM175A gene mutations were evaluated using the next generation sequencing method. The effect of gene mutations on metastasis and overall survival were evaluated. Results: The mean age of patients with colon cancer without distant metastasis was 48.64±14.72 years and for patients with distance metases was 56.68±11.65. The mean survival time of colon cancer patients with distant organ metastasis after the metastasis date was 104.36±58.59 weeks. The presence of APC, MUTYH, and TP53 genetic mutations was observed with a higher rate in metastatic colon cancer (p<0.05). Conclusion: We showed that APC, MUTYH, and TP53 mutations are associated with distant organ metastasis.     

Genomic clustering analysis identifies molecular subtypes of thymic epithelial tumors independent of World Health Organization histologic type

Further characterization of thymic epithelial tumors (TETs) is needed. Genomic information from 102 evaluable TETs from The Cancer Genome Atlas (TCGA) dataset and from the IU-TAB-1 cell line (type AB thymoma) underwent clustering analysis to identify molecular subtypes of TETs. Six novel molecular subtypes (TH1-TH6) of TETs from the TCGA were identified, and there was no association with WHO histologic subtype. The IU-TAB-1 cell line clustered into the TH4 molecular subtype and in vitro testing of candidate therapeutics was performed. The IU-TAB-1 cell line was noted to be resistant to everolimus (mTORC1 inhibitor) and sensitive to nelfinavir (AKT1 inhibitor) across the endpoints measured. Sensitivity to nelfinavir was due to the IU-TAB-1 cell line’s gain-of function (GOF) mutation in PIK3CA and amplification of genes observed from array comparative genomic hybridization (aCGH), including AURKA, ERBB2, KIT, PDGFRA and PDGFB, that are known upregulate AKT, while resistance to everolimus was primarily driven by upregulation of downstream signaling of KIT, PDGFRA and PDGFB in the presence of mTORC1 inhibition. We present a novel molecular classification of TETs independent of WHO histologic subtype, which may be used for preclinical validation studies of potential candidate therapeutics of interest for this rare disease.