Cell lineage analysis of acute leukemia relapse uncovers the role of replication-rate heterogeneity and microsatellite instability

Human cancers display substantial intratumoral genetic heterogeneity, which facilitates tumor survival under changing microenvironmental conditions. Tumor substructure and its effect on disease progression and relapse are incompletely understood. In the present study, a high-throughput method that uses neutral somatic mutations accumulated in individual cells to reconstruct cell lineage trees was applied to hundreds of cells of human acute leukemia harvested from multiple patients at diagnosis and at relapse. The reconstructed cell lineage trees of patients with acute myeloid leukemia showed that leukemia cells at relapse were shallow (divide rarely) compared with cells at diagnosis and were closely related to their stem cell subpopulation, implying that in these instances relapse might have originated from rarely dividing stem cells. In contrast, among patients with acute lymphoid leukemia, no differences in cell depth were observed between diagnosis and relapse. In one case of chronic myeloid leukemia, at blast crisis, most of the cells at relapse were mismatch-repair deficient. In almost all leukemia cases, > 1 lineage was observed at relapse, indicating that diverse mechanisms can promote relapse in the same patient. In conclusion, diverse relapse mechanisms can be observed by systematic reconstruction of cell lineage trees of patients with leukemia.     

Regeneration of the periodontium using enamel matrix derivative in combination with an injectable bone cement

Objectives

Enamel matrix derivative (EMD) has proven to enhance periodontal regeneration; however, its effect is mainly restricted to the soft periodontal tissues. Therefore, to stimulate not only the soft tissues, but also the hard tissues, in this study EMD is combined with an injectable calcium phosphate cement (CaP; bone graft material). The aim was to evaluate histologically the healing of a macroporous CaP in combination with EMD.

Materials and methods

Intrabony, three-wall periodontal defects (2?×?2?×?1.7 mm) were created mesial of the first upper molar in 15 rats (30 defects). Defects were randomly treated according to one of the three following strategies: EMD, calcium phosphate cement and EMD, or left empty. The animals were killed after 12 weeks, and retrieved samples were processed for histology and histomorphometry.

Results

Empty defects showed a reparative type of healing without periodontal ligament or bone regeneration. As measured with on a histological grading scale for periodontal regeneration, the experimental groups (EMD and CaP/EMD) scored equally, both threefold higher compared with empty defects. However, most bone formation was measured in the CaP/EMD group; addition of CAP to EMD significantly enhanced bone formation with 50 % compared with EMD alone.

Conclusions

Within the limits of this animal study, the adjunctive use of EMD in combination with an injectable cement, although it did not affect epithelial downgrowth, appeared to be a promising treatment modality for regeneration of bone and ligament tissues in the periodontium.

Clinical relevance

The adjunctive use of EMD in combination with an injectable cement appears to be a promising treatment modality for regeneration of the bone and ligament tissues in the periodontium.     

Functioning of Obese Individuals in Pre- and Postoperative Periods of Bariatric Surgery

Background

Obesity is a pathologic condition that causes functional incapacity, with reduction of quality of life and life expectancy and an increase in mortality. Bariatric surgery is indicated to alleviate associated comorbidities and increase physical capacity. The objective of this work was to evaluate the functional capacity of patients with morbid obesity before and after (3 months) bariatric surgery.

Methods

This was a cross-sectional study involving 67 patients, where 61 were women and six men, with a mean age of 38?±?10 years and mean BMI of 50.45?±?8.5 kg/m². All patients were assessed before surgery and 3 months afterwards. The following assessments were performed: 6-min walk test (6MWT), functional independence measure (FIM), and test for risk of falling and transfer capacity, called the timed up-and-go test.

Results

The study demonstrated a reduction in parameters evaluated in 6MWT with a statistically significant difference at two times (rest and final) when evaluated before and after bariatric surgery (p?<?0.001). In relation to the FIM and timed up-and-go test, the patients showed a statistically significant improvement (p?<?0.001) for both when comparing the tasks evaluated at the pre- and postoperative moments.

Conclusions

Obesity has an impact on the functioning and quality of life of patients. We observed an improvement in all instruments used for assessment before and after bariatric surgery, where a linear component was demonstrated in relation to diminution of body mass index and functioning.     

Infection of orthopedic implants and the use of antibiotic-loaded bone cements: A review

Infections by bacteria are a serious complication following orthopedic implant surgery, that can usually only be cured by removing the implant, since the biofilm mode of growth of infecting bacteria on an implant surface protects the organisms from the host immune system and antibiotic therapy. Over the past few decades, attempts have been made to prevent and cure orthopedic implant infections by incorporating antibiotics in polymethylmethacrylate bone cements, in primary and revision surgery. However, the clinical efficacy of antibiotic-releasing bone cements is not accepted by all and the long-term exposure to low doses from antibiotic-releasing bone cements in patients is strongly related to the emerging threat of antibiotic resistance in medicine today. In this article, we start by reviewing the mechanisms governing the formation of an infectious biofilm on orthopedic implant materials, the release mechanisms and properties of clinically-used, antibiotic-loaded bone cements. The clinical efficacy of antibiotic-loaded bone cements is evaluated analyzing separatedly the prophylactic and therapeutic uses of these products.     

Evaluation of tumour hypoxia during radiotherapy using [<Superscript>18</Superscript>F]HX4 PET imaging and blood biomarkers in patients with head and neck cancer

Background and purpose

Increased tumour hypoxia is associated with a worse overall survival in patients with head and neck squamous cell carcinoma (HNSCC). The aims of this study were to evaluate treatment-associated changes in [¹⁸F]HX4-PET, hypoxia-related blood biomarkers, and their interdependence.

Material and methods

[¹⁸F]HX4-PET/CT scans of 20 patients with HNSCC were acquired at baseline and after ±20Gy of radiotherapy. Within the gross-tumour-volumes (GTV; primary and lymph nodes), mean and maximum standardized uptake values, the hypoxic fraction (HF) and volume (HV) were calculated. Also, the changes in spatial uptake pattern were evaluated using [¹⁸F]HX4-PET/CT imaging. For all patients, the plasma concentration of CAIX, osteopontin and VEGF was assessed.

Results

At baseline, tumour hypoxia was detected in 69 % (22/32) of the GTVs. During therapy, we observed a significant decrease in all image parameters. The HF decreased from 21.7?±?19.8 % (baseline) to 3.6?±?10.0 % (during treatment; P?<?0.001). Only two patients had a HV?>?1 cm³ during treatment, which was located for >98 % within the baseline HV. During treatment, no significant changes in plasma CAIX or VEGF were observed, while osteopontin was increased.

Conclusions

[¹⁸F]HX4-PET/CT imaging allows monitoring changes in hypoxia during (chemo)radiotherapy whereas the blood biomarkers were not able to detect a treatment-associated decrease in hypoxia.