Rucaparib in the landscape of PARP inhibition in ovarian cancer

Introduction: The landscape of poly (ADP-ribose) polymerase (PARP) inhibition in ovarian cancer is rapidly evolving and becoming increasingly complex. Ovarian cancer is leading therapeutic innovation by providing the proof of concept for DNA repair as a target. Three different PARP inhibitors have now received approvals in the US and Europe in different indications. Subtle but crucial differences can be found among the licensed indications for each PARP inhibitor in terms of histology, type of BRCA mutation (germline and/or somatic), number of prior lines of chemotherapy and whether the indication is in the treatment or maintenance settings.

Areas covered: We review the latest clinical data regarding the PARP inhibitor rucaparib in ovarian cancer, provide an update on the evolving landscape of PARP inhibition in ovarian cancer, and summarize avenues of ongoing and future research.

Expert opinion: All eligible patients should be offered a PARP inhibitor. SOLO1 trial results demonstrated an unprecedented benefit maintenance with PARP inhibitors in first line. Results from trials evaluating PARP inhibitors as maintenance in first line regardless of BRCA status and from trials evaluating combinatorial strategies are eagerly awaited.     

Compressed sensing with signal averaging for improved sensitivity and motion artifact reduction in fluorine‐19 MRI

Fluorine‐19 (¹⁹F) MRI of injected perfluorocarbon emulsions (PFCs) allows for the non‐invasive quantification of inflammation and cell tracking, but suffers from a low signal‐to‐noise ratio and extended scan time. To address this limitation, we tested the hypotheses that a ¹⁹F MRI pulse sequence that combines a specific undersampling regime with signal averaging has both increased sensitivity and robustness against motion artifacts compared with a non‐averaged fully sampled pulse sequence, when both datasets are reconstructed with compressed sensing. As a proof of principle, numerical simulations and phantom experiments were performed on selected variable ranges to characterize the point spread function of undersampling patterns, as well as the vulnerability to noise of undersampling and reconstruction parameters with paired numbers of x signal averages and acceleration factor x (NAx ‐AFx ). The numerical simulations demonstrated that a probability density function that uses 25% of the samples to fully sample the k‐space central area allowed for an optimal balance between limited blurring and artifact incoherence. At all investigated noise levels, the Dice similarity coefficient (DSC) strongly depended on the regularization parameters and acceleration factor. In phantoms, the motion robustness of an NA8‐AF8 undersampling pattern versus NA1‐AF1 was evaluated with simulated and real motion patterns. Differences were assessed with the DSC, which was consistently higher for the NA8‐AF8 compared with the NA1‐AF1 strategy, for both simulated and real cyclic motion patterns (P < 0.001). Both strategies were validated in vivo in mice (n = 2) injected with perfluoropolyether. Here, the images displayed a sharper delineation of the liver with the NA8‐AF8 strategy than with the NA1‐AF1 strategy. In conclusion, we validated the hypotheses that in ¹⁹F MRI the combination of undersampling and averaging improves both the sensitivity and the robustness against motion artifacts.     

Mechanochemical Endovenous Ablation of Varicose Veins in Pediatric Patients with Klippel-Trénaunay Syndrome: Feasibility,Safety, and Initial Results

PurposeTo evaluate feasibility, safety, and results of endovenous mechanochemical ablation (MOCA) for treatment of persistent embryonic and dysplastic veins in pediatric patients with Klippel-Trénaunay syndrome (KTS).Materials and MethodsThirteen MOCA procedures were performed in 11 patients (age range, 4–16 years) with KTS and symptomatic persistent embryonic or dysplastic veins during a 24-month period. All patients were evaluated with color Doppler (CD) ultrasound (US), contrast-enhanced MR imaging, and venography to assess the anatomy of the target vessels and patency of the deep venous system. All procedures were performed under general anesthesia with a ClariVein catheter and liquid sodium tetradecyl sulfate as the sclerosing agent. US and fluoroscopic guidance were used in all cases. Technical success rate, primary occlusion rate, adverse effects, and recanalization rates were evaluated. Clinical and radiological (CD US) controls were performed 1 day, 7 days, 1 month, and 6 months after the procedure and once a year thereafter, with a mean follow-up of 16 months (range, 6–25 months).ResultsTechnical success and primary occlusion were achieved in all patients with no adverse events. During the follow-up period, CD US demonstrated partial recanalization and symptom recurrence in 2 patients (18%), 14 and 18 months after the initial procedure. These 2 patients had a second ablation procedure with no recanalization or symptom recurrence during the subsequent follow-up period.ConclusionsMOCA is feasible and appears to be a safe and effective technique for treatment of varicose veins in pediatric patients with KTS.     

Identification of international metastatic renal cell carcinoma database consortium (IMDC) intermediate-risk subgroups in patients with metastatic clear-cell renal cell carcinoma

Majority of patients with clear-cell renal cell carcinoma (ccRCC) at first line (1L) treatment are classified in the intermediate-risk (IR) subgroup according to International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) score. As these patients have different prognosis, the aim of this study is to better characterize IR patients in order to better tailor the treatment. Retrospective analysis was performed from IGReCC (Institut Gustave Roussy Renal Cell Carcinoma) database. Overall survival (OS) was defined from start of 1L therapy to death or last follow-up. A multivariable Cox model with backward selection procedure (α = 0.01) and a Classification and Regression Tree (CART) analysis were performed to identify which prognostic factors were associated to OS in IR patients.From 2005 to 2017, 777 patients with ccRCC were treated with an anti-VEGF 1L therapy. Among 571 evaluable patients for IMDC score, 290 (51%) were classified as IR. With median follow-up 5.8 years (min: 0, max: 12.4) 212 deaths (73%) were observed and median OS was 25 months. Only platelet count was significantly associated to OS (hazard ratio 1.88 [95% CI 1.27–2.88] p = 0.0017). Median OS for patients with PLT > UNL was 18 months [95% CI 12–23] versus 29 months [95% CI 21.4–35.7] for patients with normal PLT count. The selection of PLT count was confirmed on bootstrap samples and was also selected for the first split of the CART-tree analysis.Patients in the IR group have a heterogeneous prognosis. Elevated PLT count seems identifies a subgroup of patients with poor outcome in the IMDC intermediate-risk population with ccRCC.     

Comparison of interfaces between a NiCr alloy and various dental ceramics using transmission electron microscopy (TEM) and 3-point bending test

Several methods (e.g. tensile strength, shear bond strength) have been used in testing metal-ceramic bonds. However, in the interface, structural and analytical investigations can be applied in determining the chemical and phase structure of substances making up the bond. The aim of the present study is to assess the interface between Wiron 99 (Bego) alloy and Vision (Wohlwend) VITA VMK68 (Vita), Carat (Dentsply/DeTrey) ceramic using transmission electron microscopy (TEM) and 3-point bending test. In the case of NiCr alloys, morphologically similar but structurally varying phases developed in all of the ceramics. In each case, a Cr2O3 layer consisting of small crystals (10-20 nm) was noticed with a series of underlying bubble-like amorphous inclusions. The exact three dimensional (3D) location of these structures and their relation to the glass-phase of the ceramic, as well as its role in the nanomechanical anchoring of the ceramic are still to be clarified. The values of debonding stress were 41.67 +/- 5.01 MPa, 52.89 +/- 8.06 MPa and 56.58 +/- 10.21 MPa for Carat, VITA VMK68 ceramic and Vision, respectively. These parameters do not present significant difference at p > or = 0.05 among the three types of ceramics. Based on our measurements it is highly likely that the micromorphology of interface is basically determined by the composition of the alloy while in the chemical composition of the newly developed phases the ceramic and the parameters of firing (temperature, magnitude of vacuum and firing time) play an important role. Values of cracking and morphological resemblance suggest that the superficial micromorphological and nanomorphological structures, acting as mechanical anchoring elements, play an important role in fixing the ceramic.     

Measurement of periapical pressure created by occlusal loading

The aim of this study was to develop an in vitro model in which the pressure in the periapical tissues can be measured during loading. Extracted human maxillary central incisors were embedded into resin blocks that had physical characteristics similar to bone and periodontal ligament. Each tooth was loaded with 20, 40, 50, 60, 75, 85, 100, 200, 300 and 450 N vertical forces from the incisal edge of the crown; this procedure was carried out three consecutive times. A minute resistor embedded in the periapical space was used to detect apical pressure changes during occlusal loading. The ratio of apical pressure changes (delta P) to the loading force changes (delta F) was calculated. The periapical pressure detected was in direct proportion to the loading force. The mean value of delta P/delta F was 5.994 kPa/N (SD = 2.04). Direct proportionality was found between the coronal loading and the apical hydrostatic pressure. The (delta P)/(delta F) ratio determined in this study makes it easier to estimate the apical hydrostatic pressure values during occlusal loading of single rooted teeth. In this study the apical pressure generated under occlusal loading was of the same magnitude as that estimated with the finite element method.     

Endophthalmitis after intravitreal injections versus cataract surgery: a 15-year cohort

To compare the clinical features, visual outcomes and causative organisms between endophthalmitis secondary to cataract surgery or to intravitreal injections (IVI). Meir Medical Center, Kfar Saba, Israel. Retrospective, non-randomized comparative chart review. Medical records of patients with proven or suspected endophthalmitis admitted to the Ophthalmology Department at Meir Medical Center 2/2002–2/2017 were reviewed. Clinical characteristics including presenting and final visual acuity (VA) outcomes, causative organisms and time to admission were assessed. Among 84 patients in our study, 35 had preceding cataract surgery and 12 had preceding IVI. The post-cataract group showed a significant improvement in VA following treatment with a presenting and final VA (logMar ± SD) of (1.80 ± 0.54 and 1.39 ± 0.65, P < 0.01) as opposed to the post-IVI group (1.72 ± 0.26 and 1.81 ± 0.32, P = 0.692), while most patients in the cataract group exhibited some degree of VA recovery (70.96%). Patients undergoing cataract surgery were divided into two separate groups; those who underwent cataract surgery in a private center and those operated at a public center. Patients undergoing surgery at a private medical center showed improvement in VA outcomes following treatment (1.80 ± 0.57 and 1.13 ± 0.66, P < 0.01) as opposed to those operated on at our public medical center. Overall, patients with endophthalmitis following cataract surgery had better visual outcomes and were more likely to show a VA improvement following treatment when compared with endophthalmitis following IVI. Final VA outcomes of patients with endophthalmitis after cataract surgery performed in a private center were better than those operated on and treated in a public medical center.     

Carnosic acid ameliorates depressive‐like symptoms along with the modulation of FGF9 in the hippocampus of middle carotid artery occlusion‐induced Sprague Dawley rats

The increased survival rate of stroke patients has led to the higher incidences of post‐stroke depression. Carnosic acid has the ability to cross blood brain barrier with good neuro‐modulatory actions. Recently, inclined level of fibroblast growth factor 9 (FGF9) in the postmortem brain of the depressed patients was noted. Therefore, in the present study, the effect of carnosic acid on post‐stroke depression‐like behavior, and the expression of FGF9 were evaluated. After 3 weeks of middle carotid artery occlusion in Sprague Dawley rats, carnosic acid (20 and 40 mg/kg) was administered for 2 weeks. Sucrose preference test, forced swimming test, and open field test were performed and hippocampi were analyzed for FGF9 and FGFR‐3. In comparison to post‐stroke depressed rats, carnosic acid increased the sucrose preference, and reduced the immobility time of the rats by ~2×. The speed and distance‐covered were also increased. At 40 mg/kg, FGF9 was reduced by ~3× while FGFR‐3/Actin was increased by ~1.5×. Altogether results suggest anti‐depressant‐like activity of carnosic acid in post‐stroke depressed rats with decreased expression of hippocampal FGF9.