Allogeneic Vγ9Vδ2 T-cell immunotherapy exhibits promising clinical safety and prolongs the survival of patients with late-stage lung or liver cancer

Vγ9Vδ2 T cells are promising candidates for cellular tumor immunotherapy. Due to their HLA-independent mode of action, allogeneic Vγ9Vδ2 T cells can be considered for clinical application. To apply allogeneic Vγ9Vδ2 T cells in adoptive immunotherapy, the methodology used to obtain adequate cell numbers with optimal effector function in vitro needs to be optimized, and clinical safety and efficacy also need to be proven. Therefore, we developed a novel formula to improve the expansion of peripheral γδ T cells from healthy donors. Then, we used a humanized mouse model to validate the therapeutic efficacy of expanded γδ T cells in vivo; furthermore, the expanded γδ T cells were adoptively transferred into late-stage liver and lung cancer patients. We found that the expanded cells possessed significantly improved immune effector functions, including proliferation, differentiation, and cancer cell killing, both in vitro and in the humanized mouse model. Furthermore, a phase I clinical trial in 132 late-stage cancer patients with a total of 414 cell infusions unequivocally validated the clinical safety of allogeneic Vγ9Vδ2 T cells. Among these 132 patients, 8 liver cancer patients and 10 lung cancer patients who received ≥5 cell infusions showed greatly prolonged survival, which preliminarily verified the efficacy of allogeneic Vγ9Vδ2 T-cell therapy. Our clinical studies underscore the safety and efficacy of allogeneic Vγ9Vδ2 T-cell immunotherapy, which will inspire further clinical investigations and eventually benefit cancer patients.     

The influence of small field output factors simulated uncertainties on the calculated dose in VMAT plans for brain metastases: a multicentre study

Objectives:This multicentric study was carried out to investigate the impact of small field output factors (OFs) inaccuracies on the calculated dose in volumetric arctherapy (VMAT) radiosurgery brain plans.Methods:Nine centres, realised the same five VMAT plans with common planning rules and their specific clinical equipment Linac/treatment planning system commissioned with their OFs measured values (OFbaseline). In order to simulate OFs errors, two new OFs sets were generated for each centre by changing only the OFs values of the smallest field sizes (from 3.2 × 3.2 cm² to 1 × 1 cm²) with well-defined amounts (positive and negative). Consequently, two virtual machines for each centre were recommissioned using the new OFs and the percentage dose differences ΔD (%) between the baseline plans and the same plans recalculated using the incremented (OFup) and decremented (OFdown) values were evaluated. The ΔD (%) were analysed in terms of planning target volume (PTV) coverage and organs at risk (OARs) sparing at selected dose/volume points.Results:The plans recalculated with OFdown sets resulted in higher variation of doses than baseline within 1.6 and 3.4% to PTVs and OARs respectively; while the plans with OFup sets resulted in lower variation within 1.3% to both PTVs and OARs. Our analysis highlights that OFs variations affect calculated dose depending on the algorithm and on the delivery mode (field jaw/MLC‐defined). The Monte Carlo (MC) algorithm resulted significantly more sensitive to OFs variations than all of the other algorithms.Conclusion:The aim of our study was to evaluate how small fields OFs inaccuracies can affect the dose calculation in VMAT brain radiosurgery treatments plans. It was observed that simulated OFs errors, return dosimetric calculation accuracies within the 3% between concurrent plans analysed in terms of percentage dose differences at selected dose/volume points of the PTV coverage and OARs sparing.Advances in knowledge:First multicentre study involving different Planning/Linacs about undetectable errors in commissioning output factor for small fields.     

Neuroanatomical associations of the Edinburgh cognitive and Behavioural ALS screen (ECAS)

Brain Imaging and Behavior - Cognitive impairment is now recognized in a subset of patients with amyotrophic lateral sclerosis (ALS). The objective of the study was to identify group differences...     

What German dentists choose for their teeth: A Web-based survey of molar restorations and their longevity

Statement of problemWhich restorative material is best suited for treating the posterior molar region is unclear. As dentists presumably choose the most appropriate restoration, German dentists were asked how their own molars were treated.PurposeThe purpose of this survey study was to examine molar restorations and their durability in German dentists.Material and methodsIn the official journal of the Federal Dental Association, German dentists were asked to participate in an online survey that gathered demographic data and information on the type and durability of their molar restorations. To reduce selection bias, the data were weighted for region, sex, and age of the dentist.ResultsThe data set consisted of 1719 molars from 288 dentists. Restorations included gold inlays (25%), composite resin (24.3%), amalgam (11.8%), ceramic inlays (5.4%), glass ionomer cement or compomer (0.8%), gold crowns (21.8%), ceramic crowns (6.6%), and metal-ceramic crowns (4.3%). Notable differences were identified based on the sex, age, and region of the dentist. Women selected increased esthetic options, as did young dentists. Restorations made of gold, amalgam, and base metal had the highest longevity, at more than 20 yearsConclusionsAmong German dentists, restorations with metallic materials dominated in molars, with gold accounting for the largest share. In recent years, the proportion of tooth-colored restorations has increased, and in particular, young dentists use composite resin and ceramics.     

Patient attitude and habits regarding removable denture home hygiene and correlation with prosthesis cleanliness: A cross-sectional study of elderly Italians

Statement of problemWith the aging population, an increasing number of patients will require removable dental prostheses. Despite the recent public efforts to improve oral healthcare, knowledge of hygiene procedures for removable dental prostheses is sparse.PurposeThe purpose of this cross-sectional study was to determine, through questionnaires, the level of awareness and education of home hygiene procedures among elderly Italian individuals wearing removable dental prostheses and to correlate self-reported hygiene habits and prosthesis cleanliness, as determined by a clinical examination.Material and methodsA cross-sectional study was performed by questionnaires administered by a dental hygienist to patients attending the dental clinics (prosthodontic and periodontology clinical units) at San Paolo Hospital of Milan from January 2014 to October 2015 and who volunteered to participate. The questionnaire included demographic data and oral hygiene habits. Each participant received an intraoral and prosthesis examination performed by the same dental hygienist. The cleanliness of the removable dental prosthesis was classified according to a 3-point scoring system. Categorical variables were expressed as a percentage of study participants and compared by using the χ² test, while, for the statistical correlations between continuous and categorical variables, the point-biserial correlation calculator was used (α=.05).ResultsQuestionnaires were collected from 161 study participants: 92 women (mean ±standard deviation age: 76 ±7.59 years; range: 65-93 years) and 69 men (mean ±standard deviation age: 74 ±6.31 years; range: 65-86 years). A total of 239 prostheses were considered. A significant correlation was found between older participants, older removable dental prostheses, and reduced prosthesis cleanliness, correlating age ranges of participants as well as of removable dental prostheses with the degrees of prosthesis cleanliness (P=.001 and P=.004, respectively). Half the study participants (n=81; 50.3%) reported prosthesis removal during the night, while the others reported sleeping with the prosthesis in place. Some study participants (n=32; 19.9%) reported that they had never received instructions about how to clean the prosthesis. Mechanical brushing with toothbrush and toothpaste was the most common cleaning method (n=47; 29.2%), while the recommended combined cleaning method based on both mechanical brushing and immersion in dental cleanser was applied by 34 (21.1%) study participants. A similar number (n=25; 15.5%) reported at least 1 episode of denture-related stomatitis.ConclusionsIn the analyzed cohort, patient attitude and habits toward home procedures for denture hygiene resulted in poor prosthesis cleanliness. Most individuals used a toothbrush and toothpaste to clean their device, although combining mechanical and chemical cleaning is typically reported to be the optimal method.     

Incidental findings detected with panoramic radiography: prevalence calculated on a sample of 2017 cases treated at a major Italian trauma and cancer centre

Objectives

This study aimed to assess the prevalence of incidental findings, not strictly related to dentistry, viewed with panoramic radiography.

Methods

Panoramic radiographs performed between December 2013 and June 2016 were retrospectively collected. These images were analyzed, searching for incidental findings. All the information collected was statistically analysed

Results

A total of 2307 Panoramic Radiograph were analyzed and 2017 of them were included in the study. 529 incidental findings were seen: 255 (48.2%) were ESP (Elongation of Styloid Process), 167 were CAC (Carotid Artery Calcification) (31.57%), 36 were maxillary sinus pathologies (6.8%) and 71 were other incidental findings (13.42%). The total prevalence of IF was 26, 23%., CAC was 8.28% in the total population, and it was higher in women (9.82%) than men (6.54%). 48.5% of CAC were bilateral. When unilateral, the right side showed a higher right side prevalence. The prevalence of ESP was 12.64% in total population (men: 13.82%; women: 11.60%). 84.71% of ESP were bilateral and, when present unilaterally, no side difference was seen. 13.33% of the ESP appeared segmented. The prevalence of maxillary sinus pathologies was 1.78% (men: 2.32%; women: 1.31%). Only 8.33% of these pathologies were bilateral, and, when unilateral, they were mostly present on the right side. Between the 71 other IF (prevalence: 3.52%), sialoliths and tonsilloliths were assessed most frequently.

Conclusion

Due to the high prevalence of incidental findings detected with panoramic radiography, dental practitioners should be aware of the various pathologic conditions seen on the panoramic radiographs.

     

Dilution of candidates: the case of iron-related genes in restless legs syndrome

Restless legs syndrome (RLS) is a common multifactorial disease. Some genetic risk factors have been identified. RLS susceptibility also has been related to iron. We therefore asked whether known iron-related genes are candidates for association with RLS and, vice versa, whether known RLS-associated loci influence iron parameters in serum. RLS/control samples (n=954/1814 in the discovery step, 735/736 in replication 1, and 736/735 in replication 2) were tested for association with SNPs located within 4 Mb intervals surrounding each gene from a list of 111 iron-related genes using a discovery threshold of P=5 × 10⁻⁴. Two population cohorts (KORA F3 and F4 with together n=3447) were tested for association of six known RLS loci with iron, ferritin, transferrin, transferrin-saturation, and soluble transferrin receptor. Results were negative. None of the candidate SNPs at the iron-related gene loci was confirmed significantly. An intronic SNP, rs2576036, of KATNAL2 at 18q21.1 was significant in the first (P=0.00085) but not in the second replication step (joint nominal P-value=0.044). Especially, rs1800652 (C282Y) in the HFE gene did not associate with RLS. Moreover, SNPs at the known RLS loci did not significantly affect serum iron parameters in the KORA cohorts. In conclusion, the correlation between RLS and iron parameters in serum may be weaker than assumed. Moreover, in a general power analysis, we show that genetic effects are diluted if they are transmitted via an intermediate trait to an end-phenotype. Sample size formulas are provided for small effect sizes.     

A Post‐Hoc Comparison of the Utility of Sanger Sequencing and Exome Sequencing for the Diagnosis of Heterogeneous Diseases

The advent of massive parallel sequencing is rapidly changing the strategies employed for the genetic diagnosis and research of rare diseases that involve a large number of genes. So far it is not clear whether these approaches perform significantly better than conventional single gene testing as requested by clinicians. The current yield of this traditional diagnostic approach depends on a complex of factors that include gene‐specific phenotype traits, and the relative frequency of the involvement of specific genes. To gauge the impact of the paradigm shift that is occurring in molecular diagnostics, we assessed traditional Sanger‐based sequencing (in 2011) and exome sequencing followed by targeted bioinformatics analysis (in 2012) for five different conditions that are highly heterogeneous, and for which our center provides molecular diagnosis. We find that exome sequencing has a much higher diagnostic yield than Sanger sequencing for deafness, blindness, mitochondrial disease, and movement disorders. For microsatellite‐stable colorectal cancer, this was low under both strategies. Even if all genes that could have been ordered by physicians had been tested, the larger number of genes captured by the exome would still have led to a clearly superior diagnostic yield at a fraction of the cost.     

High frequency of MYC gene amplification is a common feature of radiation‐induced sarcomas. Further results from EORTC STBSG TL 01/01

Irradiation is a major causative factor among the small subgroup of sarcomas with a known etiology. The prognosis of radiation‐induced sarcomas (RIS) is significantly worse than that of their spontaneous counterparts. The most frequent histological subtypes include undifferentiated pleomorphic sarcomas, angiosarcomas, and leiomyosarcomas. A high frequency of MYC amplifications in radiation‐induced angiosarcomas, but not in primary angiosarcomas, has recently been described. To investigate whether MYC amplifications are also frequent in RIS other than angiosarcomas, we analyzed the MYC amplification status of 83 RIS and 192 sporadic sarcomas by fluorescence in situ hybridization. We found significantly higher numbers of MYC amplifications in RIS than in sporadic sarcomas (P < 0.0001), especially in angiosarcomas, undifferentiated pleomorphic sarcomas, and leiomyosarcomas. Angiosarcomas were special in that MYC amplifications were particularly frequent and always high level, while other RIS showed low‐level amplifications. We conclude that MYC amplifications are a frequent feature of RIS as a group and may contribute to the biology of these tumors. © 2012 Wiley Periodicals, Inc.     

Prediction of surface area size in orbital floor and medial orbital wall fractures based on topographical subregions

ObjectiveThis retrospective study evaluates the occurrence and frequency of different fracture patterns in a series of computed tomography (CT) scans in terms of the AOCMF Trauma Classification (TC) orbit module and correlates the assigned defects with measurements of the fracture area in order to get an approximate guideline for fracture size predictions on the basis of the classification.Material and methodsCT scans of patients with orbital floor fractures were evaluated using the AOCMFTC to determine the topographical subregions. The coding consisted of: W = orbital wall, 1 = anterior orbit, 2 = midorbit, i = inferior, m = medial. The 3-dimensional surface area size of the fractures was quantified by the “defect body” method (Brainlab, Munich, Germany). The fracture area size and its confidence and prediction interval within each topographical subregion was estimated by regression analysis.ResultsA total of 137 CT scans exhibited 145 orbital floor fractures, which were combined with 34 medial orbital wall fractures in 31 patients. The floor fractures – W1(i)2(i) (n = 86) and W1(i) (n = 19) were the most frequent patterns. Combined floor and medial wall fractures most frequently corresponded to the pattern W1 (im)2 (im) (n = 15) ahead of W1 (im) 2(i) (n = 10). The surface area size ranged from 0.11 cm² to 6.09 cm² for orbital floor and from 0.29 cm² to 5.43 cm² for medial wall fractures.The prediction values of the mean fracture area size within the subregions were computed as follows: W1(i) = 2.25 cm², W2(i) = 1.64 cm², W1(i)2(i) = 3.10 cm², W1(m) = 1.36 cm², W2(m) = 1.65 cm², W1(m)2(m) = 2.98 cm², W1 (im) = 3.35 cm², W1 (im) 2(i) = 4.63 cm², W1 (im)2(m) = 4.06 cm² and W1 (im)2 (im) = 7.16 cm².ConclusionThe AOCMFTC orbital module offers a suitable framework for topographical allocation of fracture patterns inside the infero-medial orbital cavity. The involvement of the subregions is of predictive value providing estimations of the mean 3-D fracture area size.