Gonadal development and function after immature testicular tissue banking as part of high-risk gonadotoxic treatment

Background

Experimental fertility preservation programs have been started to safeguard the future fertility of prepubertal and pubertal males requiring high-risk gonadotoxic treatment protocols. However, long-term follow-up studies evaluating the effects on their gonadal development and function related to the testicular biopsy procedure are rather limited.

Design

This two-center follow-up study (between 2002 and 2020) evaluated the gonadal development and function of a cohort of 59 prepubertal and pubertal males who have been offered immature testicular tissue banking (TTB) prior to conventional high-risk chemo- and/or radiotherapy (HR-C/R) or conditioning therapy before hematopoietic stem cell transplantation (CT-HSCT). The aim is to investigate the long-term impact of the testicular biopsy procedure and the high-risk gonadotoxic treatment. Testicular growth and the reproductive hormones luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone (T), and inhibin B (INHB) were analyzed after treatment completion, and compared between males accepting TTB and those refusing TTB (control) as well as between HR-C/R and CT-HSCT treatment protocols.

Results

Of the 59 prepubertal and pubertal males included, 25 were treated by HR-C/R and 34 required CT-HSCT. TTB was accepted for 39 males and refused for 20 males. Most patients were prepubertal at diagnosis (85%), at TTB (79%), and at treatment completion (76%), and pubertal or postpubertal at their last follow-up visit (66%). After 5.0 (1.0–13.0) years post treatment, most patients show normal testicular volumes (83%) and normal LH (89%), FSH (87%), T (87%), and INHB (79%) serum levels. The testicular biopsy procedure did not have an effect on testicular growth, LH, FSH, T, and INHB. Significantly more small postpubertal testicular volumes (p = .0278) and low INHB serum levels (p = .0130) were recorded after CT-HSCT, especially after myeloablative conditioning.

Conclusion

The clinical follow-up data demonstrate no effect related to the biopsy procedure, but a substantial risk for impaired gonadal development after high-risk gonadotoxic treatment, in particular myeloablative CT-HSCT. Longer follow-up studies with a larger study population are needed to confirm these preliminary findings.     

Digital optimization of teeth setup in an edentulous patient with partial glossectomy: A case report

The purpose of this clinical report was to describe the use of a piezographic impression associated with computer-aided design and computer-aided manufacturing (CAD–CAM) for teeth setup and of digital tools for neuro-musculo–kinetic analyses. An edentulous patient with hemiglossectomy and heavily resorbed mandible consulted for complete denture rehabilitation to improve their masticatory function and speech. Master casts, wax rims, and piezographic impression were scanned for digital prosthetic work. Two digital try-ins were performed to respect the neutral zone: try-in 1 with posterior crossbite and try-in 2 without crossbite. Muscle activity and mandibular kinetics were performed for each try-in following the MAC2 protocol (six criteria): muscular tone, contraction synchrony, contraction efficiency, interocclusal rest distance, amplitude of mandibular movement, and velocity. Try-in 2 showed better data than try-in 1 in all criteria: muscle tone (respectively 71% vs. 59%), contraction synchrony (79% vs. 75%), contraction efficiency (85% vs. 77%), an increase in range of motion of 3.3 mm, and a better velocity (0.35 ± 0.12 s vs. 0.57 ± 0.14 s, p = 0.008). The piezographic impression, in combination with CAD–CAM, allowed the comparison of two prosthetic designs and the selection of the try-in with the best neuro-musculo–kinetic results.     

Edaravone and mitochondrial transfer as potential therapeutics for vanishing white matter disease astrocyte dysfunction

Introduction

Previous research has suggested that vanishing white matter disease (VWMD) astrocytes fail to fully differentiate and respond differently to cellular stresses compared to healthy astrocytes. However, few studies have investigated potential VWMD therapeutics in monoculture patient-derived cell-based models.

Methods

To investigate the impact of alterations in astrocyte expression and function in VWMD, astrocytes were differentiated from patient and control induced pluripotent stem cells and analyzed by proteomics, pathway analysis, and functional assays, in the absence and presence of stressors or potential therapeutics.

Results

Vanishing white matter disease astrocytes demonstrated significantly reduced expression of astrocyte markers and markers of inflammatory activation or cellular stress relative to control astrocytes. These alterations were identified both in the presence and absence of polyinosinic:polycytidylic acid stimuli, which is used to simulate viral infections. Pathway analysis highlighted differential signaling in multiple pathways in VWMD astrocytes, including eukaryotic initiation factor 2 (EIF2) signaling, oxidative stress, oxidative phosphorylation (OXPHOS), mitochondrial function, the unfolded protein response (UPR), phagosome regulation, autophagy, ER stress, tricarboxylic acid cycle (TCA) cycle, glycolysis, tRNA signaling, and senescence pathways. Since oxidative stress and mitochondrial function were two of the key pathways affected, we investigated whether two independent therapeutic strategies could ameliorate astrocyte dysfunction: edaravone treatment and mitochondrial transfer. Edaravone treatment reduced differential VWMD protein expression of the UPR, phagosome regulation, ubiquitination, autophagy, ER stress, senescence, and TCA cycle pathways. Meanwhile, mitochondrial transfer decreased VWMD differential expression of the UPR, glycolysis, calcium transport, phagosome formation, and ER stress pathways, while further modulating EIF2 signaling, tRNA signaling, TCA cycle, and OXPHOS pathways. Mitochondrial transfer also increased the gene and protein expression of the astrocyte marker, glial fibrillary acidic protein (GFAP) in VWMD astrocytes.

Conclusion

This study provides further insight into the etiology of VWMD astrocytic failure and suggests edaravone and mitochondrial transfer as potential candidate VWMD therapeutics that can ameliorate disease pathways in astrocytes related to oxidative stress, mitochondrial dysfunction, and proteostasis.     

The epidemiology and management of odontomas: a European multicenter study

Oral and Maxillofacial Surgery - Odontoma is the most commonly diagnosed odontogenic tumor of the oral cavity. The objective of the present study was to assess the demographic variables, patterns,...