Associations of tissue tumor mutational burden and mutational status with clinical outcomes in KEYNOTE-042: pembrolizumab versus chemotherapy for advanced PD-L1-positive NSCLC.

BACKGROUND: We evaluated whether tissue tumor mutational burden (tTMB) and STK11, KEAP1, and KRAS mutations have clinical utility as biomarkers for pembrolizumab monotherapy versus platinum-based chemotherapy in patients with programmed death ligand 1 (PD-L1)-positive (tumor proportion score ≥1%) advanced/metastatic non-small-cell lung cancer (NSCLC) without EGFR/ALK alterations in the phase III KEYNOTE-042 trial. PATIENTS AND METHODS: This retrospective exploratory analysis assessed prevalence of tTMB and STK11, KEAP1, and KRAS mutations determined by whole-exome sequencing of tumor tissue and matched normal DNA and their associations with outcomes in KEYNOTE-042. Clinical utility of tTMB was assessed using a prespecified cut point of 175 mutations/exome. RESULTS: Of 793 patients, 345 (43.5%) had tTMB ≥175 mutations/exome and 448 (56.5%) had tTMB <175 mutations/exome. No association was observed between PD-L1 expression and tTMB. Continuous tTMB score was associated with improved overall survival (OS) and progression-free survival among patients receiving pembrolizumab (Wald test, one-sided P < 0.001) but not those receiving chemotherapy (Wald test, two-sided P > 0.05). tTMB ≥175 mutations/exome was associated with improved outcomes for pembrolizumab versus chemotherapy, whereas tTMB <175 mutations/exome was not {OS: hazard ratio, 0.62 [95% confidence interval (CI) 0.48-0.80] and 1.09 (95% CI 0.88-1.36); progression-free survival: 0.75 (0.59-0.95) and 1.27 (1.04-1.55), respectively}. Improved OS [hazard ratio (95% CI)] for pembrolizumab versus chemotherapy was observed regardless of STK11 [STK11 mutant (n = 33): 0.37 (0.16-0.86), STK11 wild-type (n = 396): 0.83 (0.65-1.05)]; KEAP1 [KEAP1 mutant (n = 64): 0.75 (0.42-1.35), KEAP1 wild-type (n = 365): 0.78 (0.61-0.99)], or KRAS [KRAS mutant (n = 69): 0.42 (0.22-0.81); KRAS wild-type (n = 232): 0.86 (0.63-1.18)] mutation status. CONCLUSION: tTMB with a cut point of ≥175 mutations/exome is a potential predictive biomarker for pembrolizumab monotherapy for advanced/metastatic PD-L1 tumor proportion score ≥1% NSCLC. Pembrolizumab is a standard first-line treatment in this setting regardless of STK11, KEAP1, or KRAS mutation status.

Evaluating the genetic consequences of population subdivision as it unfolds and how to best mitigate them: A rare story about koalas.

The genetic consequences of the subdivision of populations are regarded as significant to long-term evolution, and research has shown that the scale and speed at which this is now occurring is critically reducing the adaptive potential of most species which inhabit human-impacted landscapes. Here, we provide a rare and, to our knowledge, the first analysis of this process while it is happening and demonstrate a method of evaluating the effect of mitigation measures such as fauna crossings. We did this by using an extensive genetic data set collected from a koala population which was intensely monitored during the construction of linear transport infrastructure which resulted in the subdivision of their population. First, we found that both allelic richness and effective population size decreased through the process of population subdivision. Second, we predicted the extent to which genetic drift could impact genetic diversity over time and showed that after only 10 generations the resulting two subdivided populations could experience between 12% and 69% loss in genetic diversity. Lastly, using forward simulations we estimated that a minimum of eight koalas would need to disperse from each side of the subdivision per generation to maintain genetic connectivity close to zero but that 16 koalas would ensure that both genetic connectivity and diversity remained unchanged. These results have important consequences for the genetic management of species in human-impacted landscapes by showing which genetic metrics are best to identify immediate loss in genetic diversity and how to evaluate the effectiveness of any mitigation measures.

Molecular determinants of clinical outcomes with pembrolizumab versus paclitaxel in a randomized, open-label, phase III trial in patients with gastroesophageal adenocarcinoma.

BACKGROUND: In the phase III KEYNOTE-061 trial (NCT02370498), pembrolizumab did not significantly improve overall survival versus paclitaxel as second-line therapy for gastric/gastroesophageal junction (GEJ) adenocarcinoma with programmed death-ligand 1 (PD-L1) combined positive score (CPS) ≥1 tumors. The association of tissue tumor mutational burden (tTMB) status and clinical outcomes was determined, including the relationship with CPS and microsatellite instability-high (MSI-H) status. PATIENTS AND METHODS: In patients with whole exome sequencing (WES) data [420/592 (71%); pembrolizumab, 218; paclitaxel, 202], the association of tTMB with objective response rate (ORR; logistic regression), progression-free survival (PFS; Cox proportional hazards regression), and overall survival (OS; Cox proportional hazards regression) were measured using one-sided (pembrolizumab) and two-sided [paclitaxel] P values. tTMB was also evaluated using FoundationOne®CDx [205/592 (35%)]. Prespecified equivalent cut-offs of 175 mut/exome for WES and 10 mut/Mb for FoundationOne®CDx were used. RESULTS: WES-tTMB was significantly associated with ORR, PFS, and OS in pembrolizumab-treated (all P < 0.001) but not paclitaxel-treated patients (all P > 0.6) in univariate analysis. The area under the receiver operating characteristics curve for WES-tTMB and response was 0.68 [95% confidence interval (CI) 0.56-0.81] for pembrolizumab and 0.51 (95% CI 0.39-0.63) for paclitaxel in univariate analysis. There was low correlation between WES-tTMB and CPS in both treatment groups (r ≤ 0.16). WES-tTMB remained significantly associated with all clinical endpoints with pembrolizumab after adjusting for CPS and with PFS and OS after excluding known MSI-H tumors (n = 26). FoundationOne®CDx-tTMB demonstrated a positive association with ORR, PFS, and OS in pembrolizumab-treated patients (all P ≤ 0.003) but not PFS or OS in paclitaxel-treated patients (P > 0.1). CONCLUSION: This exploratory analysis from KEYNOTE-061 is the first to demonstrate a strong association between tTMB and efficacy with pembrolizumab but not paclitaxel in patients with gastric/GEJ adenocarcinoma in a randomized setting. Data further suggest tTMB is a significant and independent predictor beyond PD-L1 status.

[Endodontics in motion: new concepts, materials and techniques 1. Hydraulic Calcium Silicate Cements]. / Endodontologie in beweging: nieuwe concepten, materialen en technieken 1. Hydraulische calciumsilicaatcementen.

Hydraulic Calcium Silicate Cements (HCSCs) constitute a group of materials that have become increasingly popular in endodontics since the introduction of Mineral Trioxide Aggregate (MTA) in the 1990s. MTA is Portland cement to which bismuth oxide has been added to increase its radiopacity. The most important property of MTA is its capacity to set in water or a humid environment. However, MTA also has important limitations, for example, it's difficult to work with and can discolour teeth. Recently, numerous products based on HCSC chemistry, which can be considered as modifications of MTA intended to reduce its limitations, have become available on the market. Despite their potential advantages, all of these materials have their own specific limitations that are currently insufficiently known and investigated.

[Retinal detachment with retinoschisis--case report]. / Decolare de retina cu retinoschizis--caz clinic.

We present the case of a 43 year old patient diagnosed with rhegmatogenous retinal detachment and retinoschizis, a rare case of disease association. Surgery is recommended and we practice 23 gauge vitrectomy, laser retinopexy, criopexy in the periphery and internal heavy oil tamponade. Postoperatory evolution was favorable.

[Clinical and functional considerations in some cases of postoperative endophthalmitis]. / Consideratii clinice si functionale pe marginea unor cazuri de endoftalmita postoperatorie.

We present 3 cases of postsurgery endophthalmitis, with good initial operatory technique, which were admitted in our hospital within variable time, to which a second surgery was performed, with good postoperative evolution, without any inflammatory signs and preserving the eye. We analyse the pre and post-operative treatment of endophthalmitis, but also the ways to prevent the appearance of this post-operative complication.

[Ocular hypertension after surgery for retinal detachment]. / Hipertensiune intraoculara postchirurgia decolarii de retina.

This papers presents a case of a patient with retinal detachement, 3 days ago operated (posterior vitrectomy internal tamponament with silicon oil 1000) who develop increased ocular pressure following silicon oil output in the anterior chamber.

[Contusive ocular trauma--case report]. / Traumatism ocular contuziv--caz clinic.

We present the case of a 48 year old man who was admitted for the decreased visual acuity of the left eye for about 20 years, when a left sided facial trauma had occured. Clinical examination and lab exams revealed the cause of this change: ocular contusive posttraumatic status for about 20 years (anamnestic), iridodialysis, corectopie, traumatic cataract, PVR, tractional retinal detachment. Surgical treatment was warranted. We performed cataract extraction, posterior vitrectomy with laser fotocoagulation and injection of silicon oil 1000. We followed the pacient's post-operative evolution and we extracted of the silicone oil six months later. The evolution was favorable.

[Intraocular hypertension after retinal detachment surgery]. / Hipertensiune intraoculara postchirurgia decolarii de retina.

This papers presents a case of a patient with retinal detachment, 3 days ago operated (posterior vitrectomy, internal tamponament with silicon oil 1000) who developed increased ocular pressure following silicon oil output in the anterior chamber.

[Clinical and functional considerations in some cases of postoperative endophthalmitis]. / Consideratii clinice si functionale pe marginea unor cazuri de endoftalmita postoperatorie.

We present 3 cases of postsurgery endophthalmitis, with good initial operatory technique, which were admitted in our hospital within variable time, to which a second surgery was performed, with good postoperative evolution, without any inflamatory signs and preserving the eye. We analyse the pre and post-operative treatment of endophthalmitis, but also the ways to prevent the appearance of this post-operative complication.

How microbiomes can help inform conservation: landscape characterisation of gut microbiota helps shed light on additional population structure in a specialist folivore.

BACKGROUND: The koala (Phascolarctos cinereus), an iconic yet endangered specialised folivore experiencing widespread decline across Australia, is the focus of many conservation programs. Whilst animal translocation and progressive conservation strategies such as faecal inoculations may be required to bring this species back from the brink of extinction, insight into the variation of host-associated gut microbiota and the factors that shape this variation are fundamental for their success. Despite this, very little is known about the landscape variability and factors affecting koala gut microbial community dynamics. We used large scale field surveys to evaluate the variation and diversity of koala gut microbiotas and compared these diversity patterns to those detected using a population genetics approach. Scat samples were collected from five locations across South East Queensland with microbiota analysed using 16S rRNA gene amplicon sequencing. RESULTS: Across the landscape koala gut microbial profiles showed large variability, with location having a large effect on bacterial community composition and bacterial diversity. Certain bacteria were found to be significantly differentially abundant amongst locations; koalas from Noosa showed a depletion in two bacterial orders (Gastranaerophilales and Bacteroidales) which have been shown to provide beneficial properties to their host. Koala gut microbial patterns were also not found to mirror population genetic patterns, a molecular tool often used to design conservation initiatives. CONCLUSIONS: Our data shows that koala gut microbiotas are extremely variable across the landscape, displaying complex micro- and macro- spatial variation. By detecting locations which lack certain bacteria we identified koala populations that may be under threat from future microbial imbalance or dysbiosis. Additionally, the mismatching of gut microbiota and host population genetic patterns exposed important population structure that has previously gone undetected across South East Queensland. Overall, this baseline data highlights the importance of integrating microbiota research into conservation biology in order to guide successful conservation programs such as species translocation and the implementation of faecal inoculations.

[Rhegmatogenous retinal detachment--clinical case]. / Decolare de retina regmatogena--caz clinic.

We present the case of a 57 years old woman which was admitted for the amputation of the infero-nasal visual field of the right eye, change observed by the pacient for 2 weeks. Clinical examination and lab exams revealed the cause of this change: a rhegmatogenous retinal detachment in the superior temporal quadrant. Surgical treatement was warranted. We did a posterior vitrectomy with trans-scleral crioapplications and injection of silicone oil 1000. We followed the patient's evolution post-operative and we observed the development of a complicated cataract which was treated in a second surgery together with the extraction of the silicone oil. The evolution was favorable.

Fabrication of magnetite-based core-shell coated nanoparticles with antibacterial properties.

We report the fabrication of biofunctionalized magnetite core/sodium lauryl sulfate shell/antibiotic adsorption-shell nanoparticles assembled thin coatings by matrix assisted pulsed laser evaporation for antibacterial drug-targeted delivery. Magnetite nanoparticles have been synthesized and subsequently characterized by transmission electron microscopy and x-ray diffraction. The obtained thin coatings have been investigated by FTIR and scanning electron microscope, and tested by in vitro biological assays, for their influence on in vitro bacterial biofilm development and cytotoxicity on human epidermoid carcinoma (HEp2) cells.

Enamel pearls in permanent dentition: case report and micro-CT evaluation.

OBJECTIVES: To investigate the frequency, position, number and morphology of enamel pearls (EPs) using micro-CT (µCT) and to report a case of an EP mimicking an endodontic-periodontic lesion. METHODS: Cone beam CT (CBCT) was performed in a patient to evaluate a radio-opaque nodule observed on the left maxillary first molar during the radiographic examination. Additionally, 23 EPs were evaluated regarding frequency, position, number and morphology by means of µCT. The results were statistically compared using the Student's t-test for independent samples. RESULTS: 1 pearl was presented in 13 specimens, while 5 specimens presented 2 pearls. The most frequent location of the EPs was the furcation between the disto-buccal and the palatal roots of the maxillary molars. Overall, the mean major diameter, volume and surface area were 1.98 ± 0.85 mm, 1.76 ± 1.36 mm³ and 11.40 ± 7.59 mm², respectively, with no statistical difference between maxillary second and third molars (p > 0.05). In the case report, CBCT revealed an EP between the disto-buccal and the palatal roots of the maxillary first left molar associated with advanced localized periodontitis. The tooth was referred for extraction. CONCLUSIONS: EPs, located generally in the furcation area, were observed in 0.74% of the sample. The majority was an enamel-dentin pearl type and no difference was found in maxillary second and third molars regarding diameter, volume and surface area of the pearls. In this report, the EP mimicked an endodontic-periodontic lesion and was a secondary aetiological factor in the periodontal breakdown.

Functionalized magnetite silica thin films fabricated by MAPLE with antibiofilm properties.

We report on the fabrication of magnetite/salicylic acid/silica shell/antibiotics (Fe(3)O(4)/SA/SiO(2)/ATB) thin films by matrix-assisted pulsed laser evaporation (MAPLE) to inert substrates. Fe(3)O(4)-based powder have been synthesized and investigated by XRD and TEM. All thin films were studied by FTIR, SEM and in vitro biological assays using Staphylococcus aureus and Pseudomonas aeruginosa reference strains, as well as eukaryotic HEp-2 cells. The influence of the obtained nanosystems on the microbial biofilm development as well as their biocompatibility has been assessed. For optimum deposition conditions, we obtained uniform adherent films with the composition identical with the raw materials. Fe(3)O(4)/SA/SiO(2)/ATB thin films had an inhibitory activity on the ability of microbial strains to initiate and develop mature biofilms, in a strain- and antibiotic-dependent manner. These magnetite silica thin films are promising candidates for the development of novel materials designed for the inhibition of medical biofilms formed by different pathogenic agents on common substrates, frequently implicated in the etiology of chronic and hard to treat infections.