Immune system defects in DiGeorge syndrome and association with clinical course

We evaluated 18 DiGeorge syndrome (DGS) patients and aimed to investigate the immunological changes in this population. DGS patients with low naive CD4⁺T and CD8⁺T cells were defined as high‐risk (HR) patients, whereas patients with normal numbers of naive CD4⁺ and CD8⁺T cells were defined as standard risk (SR) patients. Level of serum IgM, CD3⁺ T cell counts and percentages of class‐switched memory B cells were significantly low in HR group compared to SR ones. Severe infections and persistent hypoparathyroidism were detected significantly higher in HR group. Patients with reduced percentages of class‐switched B cells had earlier onset of infection, lower blood IgM, lower CD4⁺ and CD8⁺T counts than patients with normal class‐switched memory B cells. Decreased levels of IgM were associated with low numbers of naive CD4⁺ and recent thymic emigrants T cells. Monitoring the immune changes of patients with DGS would be useful to predict the severe phenotype of disease.     

Pre-dosing with lilotomab prior to therapy with <Superscript>177</Superscript>Lu-lilotomab satetraxetan significantly increases the ratio of tumor to red marrow absorbed dose in non-Hodgkin lymphoma patients

Purpose

¹⁷⁷Lu-lilotomab satetraxetan is a novel anti-CD37 antibody radionuclide conjugate for the treatment of non-Hodgkin lymphoma (NHL). Four arms with different combinations of pre-dosing and pre-treatment have been investigated in a first-in-human phase 1/2a study for relapsed CD37+ indolent NHL. The aim of this work was to determine the tumor and normal tissue absorbed doses for all four arms, and investigate possible variations in the ratios of tumor to organs-at-risk absorbed doses.

Methods

Two of the phase 1 arms included cold lilotomab pre-dosing (arm 1 and 4; 40 mg fixed and 100 mg/m² BSA dosage, respectively) and two did not (arms 2 and 3). All patients were pre-treated with different regimens of rituximab. The patients received either 10, 15, or 20 MBq ¹⁷⁷Lu-lilotomab satetraxetan per kg body weight. Nineteen patients were included for dosimetry, and a total of 47 lesions were included. The absorbed doses were calculated from multiple SPECT/CT-images and normalized by administered activity for each patient. Two-sided Student’s t tests were used for all statistical analyses.

Results

Organs with distinct uptake of ¹⁷⁷Lu-lilotomab satetraxetan, in addition to tumors, were red marrow (RM), liver, spleen, and kidneys. The mean RM absorbed doses were 0.94, 1.55, 1.44, and 0.89 mGy/MBq for arms 1–4, respectively. For the patients not pre-dosed with lilotomab (arms 2 and 3 combined) the mean RM absorbed dose was 1.48 mGy/MBq, which was significantly higher than for both arm 1 (p?=?0.04) and arm 4 (p?=?0.02). Of the other organs, the highest uptake was found in the spleen, and there was a significantly lower spleen absorbed dose for arm-4 patients than for the patient group without lilotomab pre-dosing (1.13 vs. 3.20 mGy/MBq; p?<?0.01).Mean tumor absorbed doses were 2.15, 2.31, 1.33, and 2.67 mGy/MBq for arms 1–4, respectively. After averaging the tumor absorbed dose for each patient, the patient mean tumor absorbed dose to RM absorbed dose ratios were obtained, given mean values of 1.07 for the patient group not pre-dosed with lilotomab, of 2.16 for arm 1, and of 4.62 for arm 4. The ratios were significantly higher in both arms 1 and 4 compared to the group without pre-dosing (p?=?0.05 and p?=?0.02). No statistically significant difference between arms 1 and 4 was found.

Conclusions

RM is the primary dose-limiting organ for ¹⁷⁷Lu-lilotomab satetraxetan treatment, and pre-dosing with lilotomab has a mitigating effect on RM absorbed dose. Increasing the amount of lilotomab from 40 mg to 100 mg/m² was found to slightly decrease the RM absorbed dose and increase the ratio of tumor to RM absorbed dose. Still, both pre-dosing amounts resulted in significantly higher tumor to RM absorbed dose ratios. The findings encourage continued use of pre-dosing with lilotomab.

     

Facial asymmetry in young healthy subjects evaluated by statistical shape analysis

Statistical shape analysis, a relatively a new method for biological research, compares body forms by using specific landmarks determined by anatomical prominences. In this study, we aimed to identify normal facial asymmetry between the right and the left sides of the face. Facial landmark data were collected from two‐dimensional digital images of 321 young healthy subjects (150 males and 171 females). These data were analysed using Euclidean distance matrix analysis. The number of significantly asymmetric linear distances between the two halves of the face was greater in females than in males. We found that the left side of the face was most commonly dominant in both males and females. Such data may be useful in establishing a database for future similar studies.     

A Novel Treatment of Very Rare Anomaly; Breast Pseudoaneurysm Developed During Pregnancy

Pseudoaneurysms (PA) in the arterial supply of the breast are quite rare and mostly iatrogenic secondary to biopsies. Breast PAs after blunt trauma is even rarer. In this paper, a case of breast PAs secondary to blunt trauma and its percutaneous treatment using human thrombin injection and after N‐butyl cyanoacrylate is presented.     

Biweekly administration of gemcitabine and cisplatin chemotherapy in patients with anthracycline and taxane-pretreated metastatic breast cancer

Gemcitabine and cisplatin are the active agents in metastatic breast cancer pretreated with anthracycline and/or taxane as a second line treatment. The present study was designed to assess the efficacy and safety of this regimen given biweekly schedule in these patients. Twenty-seven women, median age 57, with metastatic breast cancer previously treated with anthracycline and taxane were eligible for enrollment. Gemcitabine was administered intravenously on days 1 and 15 at a dose of 2,000 mg/m(2) and Cisplatin was given intravenously on day 1 and 15 at a dose of 50 mg/m(2). Treatment cycles were repeated on an outpatient basis every 28 days. Of all 27 evaluable patients, the overall response rate was 26% (7 of 27; 95% CI: 11-46%) with seven all partial responses. The stable diseases were found in 9 (33%) patients. At the time of last follow-up, 11 (41%) of the patients died of their disease progression. The median overall survival duration was 7.4 +/- 2.8 months. The 1-year overall survival rate was 46.9% +/- 12.3. Hematological toxicity was not found as the principal dose-limiting toxicity. Severe (grade III/IV) neutropenia was observed only one (4%) patients. No patient was complicated by febrile neutropenia and G-CSF usage was not performed. Grade III and IV anemia were seen in only 4 (15%) and thrombocytopenia was noted only one (4%) patients. Severe hepatic (n = 2) and renal toxicity (n = 1) were observed and these all recovered completely without complication. Several other severe non-hematological side effects were managed easily. Permanent dose reductions were necessary in 9 (33%) patients and chemotherapy administration was also delayed in 7 (26%) patients because of delayed both hematological and non-hematological toxicity recovery. Treatment was discontinued in one (4%) patient due to severe fatigue and deteriorating performance status. In conclusion, gemcitabine and cisplatin combination therapy with this biweekly schedule and dosage is moderately active and extremely safe in patients with metastatic breast cancer previously treated with anthracycline and taxanes.     

Effect of oral administration of kefir on serum proinflammatory cytokines on 5-FU induced oral mucositis in patients with colorectal cancer

Summary  In order to investigate the effect of kefir consumption on mucositis induced by 5-FU based chemotherapy (CT), we monitored the systemic immune response by measurement of the serum proinflammatory cytokine levels and we evaluated the anti-microbial effect of kefir with an agar diffusion method. Forty patients with colorectal cancer were included in this randomized prospective study. On the first 5 days of each CT cycle, the study group received oral lavage with kefir and then swallowed 250 ml of kefir while control group received oral lavage with 0.09% NaCl twice a day. Before and after every cycle of CT, the oral mucosa was assessed. Serum proinflammatory cytokine levels were evaluated before the initiation and after the third and the sixth cycle. Kefir was administered in 99 out of 205 courses. Mucositis developed in 27.3% of the courses given with kefir administration and in 21.7% of the courses given with 0.9% NaCl oral rinses. The difference between the two groups was not statistically significant (p > 0.05). When we compared the serum proinflammatory cytokine levels of the two groups at the baseline and following the third and the sixth cycles, we again found no statistically significant difference (p > 0.05). Kefir consumption at the mentioned doses made no statistically significant effect on serum proinflammatory cytokine levels and on the incidence of mucositis development in cancer patients. Under in vitro conditions, kefir inhibits only Staphylococcus epidermidis.     

Novel variant p.E269K confirms causative role of PLS1 mutations in autosomal dominant hearing loss

Auditory reception relies on the perception of mechanical stimuli by stereocilia and its conversion to electrochemical signal. Mechanosensory stereocilia are abundant in actin, which provides them with structural conformity necessary for perception of auditory stimuli. Out of three major classes of actin-bundling proteins, plastin 1 encoded by PLS1, is highly expressed in stereocilia and is necessary for their regular maintenance. A missense PLS1 variant associated with autosomal dominant hearing loss (HL) in a small family has recently been reported. Here, we present another PLS1 missense variant, c.805G > A (p.E269K), in a Turkish family with autosomal dominant non-syndromic HL confirming the causative role of PLS1 mutations in HL. We propose that HL due to the p.E269K variant is from the loss of a stable PLS1-ACTB interaction.     

Modification of Surface and Subsurface Properties of AA1050 Alloy by Shot Peening

AA1050 Al alloy samples were shot-peened using stainless-steel shots at shot peening (SP) pressures of 0.1 and 0.5 MPa and surface cover rates of 100% and 1000% using a custom-designed SP system. The hardness of shot-peened samples was around twice that of unpeened samples. Hardness increased with peening pressure, whereas the higher cover rate did not lead to hardness improvement. Micro-crack formation and embedment of shots occurred by SP, while average surface roughness increased up to 9 µm at the higher peening pressure and cover rate, indicating surface deterioration. The areal coverage of the embedded shots ranged from 1% to 5% depending on the peening parameters, and the number and the mean size of the embedded shots increased at the higher SP pressure and cover rate. As evidenced and discussed through the surface and cross-sectional SEM images, the main deformation mechanisms during SP were schematically described as crater formation, folding, micro-crack formation, and material removal. Overall, shot-peened samples demonstrated improved mechanical properties, whereas sample surface integrity only deteriorated notably during SP at the higher pressure, suggesting that selecting optimal peening parameters is key to the safe use of SP. The implemented methodology can be used to modify similar soft alloys within confined compromises in surface features.