Intravitreal Carboplatin as Salvage Treatment for Progressive Vitreous Disease in Retinoblastoma: A Phase I Clinical Trial.

PURPOSE: To determine the safety and toxicity profile of intravitreal carboplatin as salvage treatment for retinoblastoma with vitreous disease. DESIGN: Single-institution, interventional prospective clinical trial. PARTICIPANTS: Patients with progressive or recurrent vitreous seeds after completion of primary treatment for intraocular retinoblastoma. METHODS: Eligible eyes received an intravitreal injection of carboplatin every 14 to 21 days with simultaneous focal therapy (laser, thermotherapy, and brachytherapy) provided at the discretion of the ocular oncologist. The evaluation with examination under anesthesia, ultrasound biomicroscopy, and electroretinography (ERG) were performed before each injection to assess for tumor response and drug-related toxicity. A serious adverse event resulted in dose recalculation and ultimately early closure of the study. MAIN OUTCOME MEASURES: Regression pattern of vitreous disease and incidence of dose-limiting toxicities. RESULTS: Four patients were enrolled at an initial dose of 0.3 mg. Complete regression of vitreous seeds was noted in all patients after 5, 2, 2, and 1 injections (respectively). Two patients developed recurrent vitreous disease at 3 and 25 months after complete regression and ultimately required enucleation. A serious adverse event occurred in 1 patient who developed acute vision loss with extinguished ERG response 72 hours after the second injection; ultimately, this eye developed a cataract and required enucleation. After temporary suspension and dose modification, 3 patients were enrolled at an injection dose of 3 µg and treated with a total of 5, 2, and 1 injections, respectively. Complete regression of vitreous disease was not achieved in any patient though ERG amplitudes remained stable. After removal from protocol, all 3 patients had a complete response to intravitreal melphalan. Concern for dose escalation and further toxicity in the setting of an effective and safe alternative (melphalan) led to the termination of the study. CONCLUSIONS: Intravitreal carboplatin may be effective in treating progressive vitreous seeding at higher doses, but permanent retinal toxicity was observed. Other alternative agents should be considered. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Radiohistogenomics of pediatric low-grade neuroepithelial tumors.

PURPOSE: In addition to histology, genetic alteration is now required to classify many central nervous system (CNS) tumors according to the most recent World Health Organization CNS tumor classification scheme. Although that is still not the case for classifying pediatric low-grade neuroepithelial tumors (PLGNTs), genetic and molecular features are increasingly being used for making treatment decisions. This approach has become a standard clinical practice in many specialized pediatric cancer centers and will likely be more widely practiced in the near future. This paradigm shift in the management of PLGNTs necessitates better understanding of how genetic alterations influence histology and imaging characteristics of individual PLGNT phenotypes. METHODS: The complex association of genetic alterations with histology, clinical, and imaging of each phenotype of the extremely heterogeneous PLGNT family has been addressed in a holistic approach in this up-to-date review article. A new imaging stratification scheme has been proposed based on tumor morphology, location, histology, and genetics. Imaging characteristics of each PLGNT entity are also depicted in light of histology and genetics. CONCLUSION: This article reviews the association of specific genetic alteration with location, histology, imaging, and prognosis of a specific tumor of the PLGNT family and how that information can be used for better imaging of these tumors.

Associations between multimorbidity, all-cause mortality and glycaemia in people with type 2 diabetes: A systematic review.

INTRODUCTION: Type 2 diabetes (T2D) is a major health priority worldwide and the majority of people with diabetes live with multimorbidity (MM) (the co-occurrence of ≥2 chronic conditions). The aim of this systematic review was to explore the association between MM and all-cause mortality and glycaemic outcomes in people with T2D. METHODS: The search strategy centred on: T2D, MM, comorbidity, mortality and glycaemia. Databases searched: MEDLINE, EMBASE, CINAHL Complete, The Cochrane Library, and SCOPUS. Restrictions included: English language, quantitative empirical studies. Two reviewers independently carried out: abstract and full text screening, data extraction, and quality appraisal. Disagreements adjudicated by a third reviewer. RESULTS: Of the 4882 papers identified; 41 met inclusion criteria. The outcome was all-cause mortality in 16 studies, glycaemia in 24 studies and both outcomes in one study. There were 28 longitudinal cohort studies and 13 cross-sectional studies, with the number of participants ranging from 96-892,223. Included studies were conducted in high or upper-middle-income countries. Fifteen of 17 studies showed a statistically significant association between increasing MM and higher mortality. Ten of 14 studies showed no significant associations between MM and HbA1c. Four of 14 studies found higher levels of MM associated with higher HbA1c. Increasing MM was significantly associated with hypoglycaemia in 9/10 studies. There was no significant association between MM and fasting glucose (one study). No studies explored effects on glycaemic variability. CONCLUSIONS: This review demonstrates that MM in T2D is associated with higher mortality and hypoglycaemia, whilst evidence regarding the association with other measures of glycaemic control is mixed. The current single disease focused approach to management of T2D seems inappropriate. Our findings highlight the need for clinical guidelines to support a holistic approach to the complex care needs of those with T2D and MM, accounting for the various conditions that people with T2D may be living with. SYSTEMATIC REVIEW REGISTRATION: International Prospective Register of Systematic Reviews CRD42017079500.

Microwave ablation in primary and secondary liver tumours: technical and clinical approaches.

Thermal ablation is increasingly being utilised in the treatment of primary and metastatic liver tumours, both as curative therapy and as a bridge to transplantation. Recent advances in high-powered microwave ablation systems have allowed physicians to realise the theoretical heating advantages of microwave energy compared to other ablation modalities. As a result there is a growing body of literature detailing the effects of microwave energy on tissue heating, as well as its effect on clinical outcomes. This article will discuss the relevant physics, review current clinical outcomes and then describe the current techniques used to optimise patient care when using microwave ablation systems.

Modeling and validation of microwave ablations with internal vaporization.

Numerical simulation is increasingly being utilized for computer-aided design of treatment devices, analysis of ablation growth, and clinical treatment planning. Simulation models to date have incorporated electromagnetic wave propagation and heat conduction, but not other relevant physics such as water vaporization and mass transfer. Such physical changes are particularly noteworthy during the intense heat generation associated with microwave heating. In this paper, a numerical model was created that integrates microwave heating with water vapor generation and transport by using porous media assumptions in the tissue domain. The heating physics of the water vapor model was validated through temperature measurements taken at locations 5, 10, and 20 mm away from the heating zone of the microwave antenna in homogenized ex vivo bovine liver setup. Cross-sectional area of water vapor transport was validated through intraprocedural computed tomography (CT) during microwave ablations in homogenized ex vivo bovine liver. Iso-density contours from CT images were compared to vapor concentration contours from the numerical model at intermittent time points using the Jaccard index. In general, there was an improving correlation in ablation size dimensions as the ablation procedure proceeded, with a Jaccard index of 0.27, 0.49, 0.61, 0.67, and 0.69 at 1, 2, 3, 4, and 5 min, respectively. This study demonstrates the feasibility and validity of incorporating water vapor concentration into thermal ablation simulations and validating such models experimentally.

Microwave ablation energy delivery: influence of power pulsing on ablation results in an ex vivo and in vivo liver model.

PURPOSE: The purpose of this study was to compare the impact of continuous and pulsed energy deliveries on microwave ablation growth and shape in unperfused and perfused liver models. METHODS: A total of 15 kJ at 2.45 GHz was applied to ex vivo bovine liver using one of five delivery methods (n = 50 total, 10 per group): 25 W continuous for 10 min (25 W average), 50 W continuous for 5 min (50 W average), 100 W continuous for 2.5 min (100 W average), 100 W pulsed for 10 min (25 W average), and 100 W pulsed for 5 min (50 W average). A total of 30 kJ was applied to in vivo porcine livers (n = 35, 7 per group) using delivery methods similar to the ex vivo study, but with twice the total ablation time to offset heat loss to blood perfusion. Temperatures were monitored 5-20 mm from the ablation antenna, with values over 60 °C indicating acute cellular necrosis. Comparisons of ablation size and shape were made between experimental groups based on total energy delivery, average power applied, and peak power using ANOVA with post-hoc pairwise tests. RESULTS: No significant differences were noted in ablation sizes or circularities between pulsed and continuous groups in ex vivo tissue. Temperature data demonstrated more rapid heating in pulsed ablations, suggesting that pulsing may overcome blood perfusion and coagulate tissues more rapidly in vivo. Differences in ablation size and shape were noted in vivo despite equivalent energy delivery among all groups. Overall, the largest ablation volume in vivo was produced with 100 W continuous for 5 min (265.7 ± 208.1 cm(3)). At 25 W average, pulsed-power ablation volumes were larger than continuous-power ablations (67.4 ± 34.5 cm(3) versus 23.6 ± 26.5 cm(3), P = 0.43). Similarly, pulsed ablations produced significantly greater length (P ≤ 0.01), with increase in diameter (P = 0.09) and a slight decrease in circularity (P = 0.97). When comparing 50 W average power groups, moderate differences in size were noted (P ≥ 0.06) and pulsed ablations were again slightly more circular. CONCLUSIONS: Pulsed energy delivery created larger ablation zones at low average power compared to continuous energy delivery in the presence of blood perfusion. Shorter duty cycles appear to provide greater benefit when pulsing.

Computational modelling of microwave tumour ablations.

Microwave tissue heating is being increasingly utilised in several medical applications, including focal tumour ablation, cardiac ablation, haemostasis and resection assistance. Computational modelling of microwave ablations is a precise and repeatable technique that can assist with microwave system design, treatment planning and procedural analysis. Advances in coupling temperature and water content to electrical and thermal properties, along with tissue contraction, have led to increasingly accurate computational models. Developments in experimental validation have led to broader acceptability and applicability of these newer models. This review will discuss the basic theory, current trends and future direction of computational modelling of microwave ablations.

Anticonvulsant serotonergic and deep brain stimulation in anterior thalamus.

OBJECTIVE: Anterior thalamus (AN) has been shown to mediate seizures in both focal and generalized models. Specific regional increase in AN serotonergic activity was observed following AN-DBS in our pentylenetetrazol (PTZ) rodent model of acute seizures, and this increase may inhibit seizures and contribute to the mechanism of anticonvulsant DBS. METHODS: Anesthetized rats with AN-directed dialysis cannula with scalp/depth EEG were infused with PTZ at 5.5mg/(kg min) until an EEG seizure occurred. Eight experimental groups of AN-dialysis infusion were evaluated: controls (dialysate-only), 10 and 100 microM serotonin 5-HT(7) agonist 5-carboxamidotryptamine (5-CT), 1, 10 and 100 microM serotonin antagonist methysergide (METH), AN-DBS, and 100 microM METH+AN-DBS. RESULTS: Latency for seizures in control animals was 3,120+/-770 s (S.D.); AN-DBS delayed onset to 5018+/-1100 (p<0.01). AN-directed 5-CT increased latency in dose-dependent fashion: 3890+/-430 and 4247+/-528 (p<0.05). Methysergide had an unexpected protective effect at low-dose (3908+/-550, p<0.05) but not at 100 microM (2687+/-1079). The anticonvulsant action of AN-DBS was blocked by prior dialysis using 100 microM METH. Surface EEG burst count and nonlinear analysis (H-Statistic) noted significant (p<0.05) increased pre-ictal epileptiform bursts in 5-CT, methysergide, but not DBS group compared to control. CONCLUSION: Increased serotonergic activity in AN raised PTZ seizure threshold, similar to DBS, but without preventing cortical bursting. 5-Carboxamidotryptamine, a 5-HT(7) agonist, demonstrated dose-dependent seizure inhibition. Methysergide proved to have an inverse, dose-dependent agonist property, antagonizing the action of AN-DBS at the highest dose. Anticonvulsant AN-DBS may in part act to selectively alter serotonin neurotransmission to raise seizure threshold.