Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) for ovarian cancer in an Australian institution: lessons from 20 years' experience.

OBJECTIVES: We report the 20-year experience of the largest Australian unit performing cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for ovarian cancer and reflect on learning opportunities. METHODS: A retrospective review of all cases of CRS for ovarian cancer at St George Peritonectomy Unit from Jan 1998 to Jan 2018 was performed. Prospectively collected data include age, stage, histology, disease extent (PCI), completeness of cytoreduction (CC score), HIPEC regime, 30-day surgical morbidity, disease recurrence, and death. Survival was computed using Kaplan-Meier method and analysed using log-rank tests and Cox-proportional hazards models. RESULTS: Forty-one women with advanced ovarian cancer (11 primary stage III/IV, 30 recurrent) underwent CRS, 29 (71%) with HIPEC. Most (68%) had high-volume disease (PCI > 15). In 98%, CC0/CC1 (residual < 2.5 mm) was achieved. Fourteen (34%) had grade 3/4 complications, 1 patient (2%) died within 30 days and 2 patients (5%) died within 90 days. Progression-free and median overall survival was 30.0 and 67.0 months for primary cancer, and 6.7 and 18.1 months for recurrent cancer. Survival was associated with platinum-sensitivity, PCI ≤ 15, and CC score 0, but not HIPEC. CONCLUSION: This study reports outcomes for patients with advanced ovarian cancer patients treated in an Australian centre offering CRS and HIPEC. Whilst survival and morbidity outcomes were good for primary disease, they were poorer than predicted from the literature for cases of recurrent disease. The incorporation of evidence-based predictors of survival and multidisciplinary input are essential to achieve the best survival outcomes.

Plasmonic gold nanostars for multi-modality sensing and diagnostics.

Gold nanostars (AuNSs) are unique systems that can provide a novel multifunctional nanoplatform for molecular sensing and diagnostics. The plasmonic absorption band of AuNSs can be tuned to the near infrared spectral range, often referred to as the "tissue optical window", where light exhibits minimal absorption and deep penetration in tissue. AuNSs have been applied for detecting disease biomarkers and for biomedical imaging using multi-modality methods including surface-enhanced Raman scattering (SERS), two-photon photoluminescence (TPL), magnetic resonance imaging (MRI), positron emission tomography (PET), and X-ray computer tomography (CT) imaging. In this paper, we provide an overview of the recent development of plasmonic AuNSs in our laboratory for biomedical applications and highlight their potential for future translational medicine as a multifunctional nanoplatform.

What patients are reading about noninvasive prenatal testing: an evaluation of Internet content and implications for patient-centered care.

OBJECTIVE: Patients' use of the Internet as a source of health information is increasing. The objective of this study was to describe and evaluate Internet-based information about noninvasive prenatal testing (NIPT), an important new genetic test currently available to high-risk women in early pregnancy. METHODS: Websites were sampled using leading search engines to mirror Internet-based search patterns of individuals seeking information about NIPT. Content analysis was conducted to assess website reading level, quality, and content. RESULTS: Basic information about NIPT use as a screening test was accurately described. Overall, sampled websites lacked balance and comprehensive information about NIPT and the complexity of decision making involved in electing for its use. All websites were written at reading levels higher than currently recommended levels for public health information. CONCLUSION: While online resources should be used with reservation, they can be an important tool to support effective communication and patient-centered care. Online information can help both health care providers and pregnant patients who face a growing number of fetal genetic testing options.

Using mechanobiological mimicry of red blood cells to extend circulation times of hydrogel microparticles.

It has long been hypothesized that elastic modulus governs the biodistribution and circulation times of particles and cells in blood; however, this notion has never been rigorously tested. We synthesized hydrogel microparticles with tunable elasticity in the physiological range, which resemble red blood cells in size and shape, and tested their behavior in vivo. Decreasing the modulus of these particles altered their biodistribution properties, allowing them to bypass several organs, such as the lung, that entrapped their more rigid counterparts, resulting in increasingly longer circulation times well past those of conventional microparticles. An 8-fold decrease in hydrogel modulus correlated to a greater than 30-fold increase in the elimination phase half-life for these particles. These results demonstrate a critical design parameter for hydrogel microparticles.

Concurrent nonavalent human papillomavirus (HPV) vaccination and immune stimulation with imiquimod to treat recalcitrant HPV-associated high grade vaginal intra-epithelial neoplasia.

This is the first report describing detailed T cell responses to viral-like proteins contained in an HPV specific vaccine given in combination with Imiquimod for treatment of persistent VAIN2/3. We postulate that stimulation of the innate immune system with Imiquimod and the specific CD4 and CD8T cell responses following HPV vaccination with Gardasil9@ combined to induce clinical remission in a woman with treatment-refractory disease.

Profiling cognitive-motor interference in a large sample of persons with progressive multiple sclerosis and impaired processing speed: results from the CogEx study.

BACKGROUND: Performing cognitive-motor dual tasks (DTs) may result in reduced walking speed and cognitive performance. The effect in persons with progressive multiple sclerosis (pwPMS) having cognitive dysfunction is unknown. OBJECTIVE: To profile DT-performance during walking in cognitively impaired pwPMS and examine DT-performance by disability level. METHODS: Secondary analyses were conducted on baseline data from the CogEx-study. Participants, enrolled with Symbol Digit Modalities Test 1.282 standard deviations below normative value, performed a cognitive single task ([ST], alternating alphabet), motor ST (walking) and DT (both). Outcomes were number of correct answers on the alternating alphabet task, walking speed, and DT-cost (DTC: decline in performance relative to the ST). Outcomes were compared between EDSS subgroups (≤ 4, 4.5-5.5, ≥ 6). Spearman correlations were conducted between the DTCmotor with clinical measures. Adjusted significance level was 0.01. RESULTS: Overall, participants (n = 307) walked slower and had fewer correct answers on the DT versus ST (both p < 0.001), with a DTCmotor of 15.8% and DTCcognitive of 2.7%. All three subgroups walked slower during the DT versus ST, with DTCmotor different from zero (p's < 0.001). Only the EDSS ≥ 6 group had fewer correct answers on the DT versus ST (p < 0.001), but the DTCcognitive did not differ from zero for any of the groups (p ≥ 0.039). CONCLUSION: Dual tasking substantially affects walking performance in cognitively impaired pwPMS, to a similar degree for EDSS subgroups.

Effect of aspect ratio and deformability on nanoparticle extravasation through nanopores.

We describe the fabrication of filamentous hydrogel nanoparticles using a unique soft lithography based particle molding process referred to as PRINT (particle replication in nonwetting templates). The nanoparticles possess a constant width of 80 nm, and we varied their lengths ranging from 180 to 5000 nm. In addition to varying the aspect ratio of the particles, the deformability of the particles was tuned by varying the cross-link density within the particle matrix. Size characteristics such as hydrodynamic diameter and persistence length of the particles were analyzed using dynamic light scattering and electron microscopy techniques, respectively, while particle deformability was assessed by atomic force microscopy. Additionally, the ability of the particles to pass through membranes containing 0.2 µm pores was assessed by means of a simple filtration technique, and particle recovery was determined using fluorescence spectroscopy. The results show that particle recovery is mostly independent of aspect ratio at all cross-linker concentrations utilized, with the exception of 96 wt % PEG diacrylate 80 × 5000 nm particles, which showed the lowest percent recovery.

Incorporation of an interferon-ß neutralizing antibody assay into routine clinical practice.

BACKGROUND: Incorporation of routine clinical testing for neutralizing antibodies (NAbs) to interferon (IFN)-ß has remained problematic. With increasing treatment choice for patients, routine NAb testing should be incorporated to aid therapeutic decisions. OBJECTIVE: We sought to improve interpretation of NAb results by combining the luciferase NAb assay (luciferase gene expression assay under control of interferon-stimulated response element) and in-vivo biomarker (myxovirus A protein, MxA) induction in patients with MS. METHODS: Blood samples (serum and PAXGene(®) for RNA) were obtained pre-injection and 12 hours post-injection of IFN-ß from 144 subjects. Sera were tested for NAbs using the luciferase assay. MxA expression was quantified by real-time polymerase chain reaction (PCR). RESULTS: 26% of samples were NAb positive (titre > 20 NU). There was no difference in NAb titres in the pre- or post-dose sera (p = 0.643). MxA expression was inhibited in a dose-dependent fashion in NAb positive samples. Mean MxA level post-IFN-ß: NAb negative 2330 (95% CI 1940-2719), NAb 20-99 NU 1533 (95% CI 741-2324), NAb 100-600 NU 832 (186-1478) and NAb > 600 NU 101 (95% CI 0-224). NAb titre and MxA level correlated strongly: MxA pre- (Spearman r = -0.72, p < 0.0001), MxA post- (Spearman r = -0.79, p < 0.0001) and MxA induction (Spearman r = -0.67, p = 0.0004). CONCLUSION: A single, 12-hour post-injection sample should be used to test for NAbs using the luciferase assay and IFN-ß bioactivity (MxA) in the clinical setting.

Evaluation of the cognitive benefits of intrathecal baclofen pump implantation in people with intractable multiple sclerosis related spasticity.

BACKGROUND: Spasticity is a common problematic symptom in Multiple Sclerosis with over one third of patients failing first line therapies. Intrathecal baclofen is a safe and efficacious option for treatment resistant spasticity. Anecdotally patients report improved concentration/cognitive performance when switching to intrathecal baclofen (ITB) from systemic medications. AIM: To explore whether subjects who proceed with ITB pump implantation for spasticity management and reduce oral anti-spasticity agents will have improved cognitive function. METHODS: Subjects were admitted for trial of ITB via lumbar puncture and subsequent pump implantation. Spasticity and cognitive measures before ITB trial and 3 months post implant were recorded. Paired t-test or Wilcoxon Signed Ranks test was used for within subject change and effect sizes (Cohen's dz) were calculated. Subgroup analysis of those on ≥2, or ≤ 1 spasticity medications at baseline was performed. RESULTS: 27 subjects with MS completed per protocol. Mean age 46 years [26 - 56], disease duration 15 years [6 - 26], RRMS = 3, SPMS = 17 and PPMS=7. The majority were on multiple spasticity medications. Spasticity scores significantly improved post pump implant. Mean ITB dose at 3 months was 143 mcg / day and 19 discontinued all other treatments for spasticity. There was no deterioration on any cognitive or mood measure. An improvement of moderate effect size was found in Backwards Digit Span (d=0.41, p=0.059) and HADS - anxiety (d=0.37, p=0.097). Fatigue Severity Scale score decreased substantially (d=0.81, p=0.005). Small improvements in Symbol Digit Modalities Test score (d=0.24) and Sustained Attention to Response Task response time (d=0.23) were non-significant. Performance on other measures did not change. Effect sizes were larger in subgroup on ≥2 oral spasticity medications at baseline, compared to the group on ≤1 medication (SDMT, d=0.42 vs d=0.07; Backwards digit span 0.45 vs 0.28; HADS-anxiety 0.39 vs 0.32; HADS-depression d=0.32 vs 0.05 and FSS, d= 1.14 vs 0.42). CONCLUSIONS: In a pilot study exploring the impact of ITB on cognition, spasticity scores improved universally and beneficial effects on some measures of fatigue, anxiety, auditory attention and verbal working memory were found. Improvement of speed of processing in those withdrawing higher doses of oral medication was also demonstrated suggesting that switching to ITB has added cognitive and psychological benefits for people with MS.

Evaluation of the impact of intrathecal baclofen on the walking ability of people with Multiple Sclerosis related spasticity.

BACKGROUND: Spasticity is a frequent and disabling symptom in people with Multiple Sclerosis (MS). Intrathecal baclofen (ITB) is an effective but infrequently used treatment in ambulant people. OBJECTIVE: To evaluate the impact of ITB on ambulation in people with moderate to severe MS related spasticity. METHODS: Data was collected prospectively regarding spasticity and ambulation at baseline, after ITB trial via lumbar puncture, 3 months and annually thereafter. RESULTS: 30 subjects; Mean age 47.9 (26-64), 67% female, mean EDSS 6.5 [6.5-7.5]. Reduction in mean Ashworth score (pre 1.44: post 0.98, p<0.001) and Penn spasm score (pre 3: post 1; p<0.001) was shown. 20 people (67%) proceeded with implantation; lower limb MRC power was predictive of proceeding to pump (OR 2.98; 95% CI 1.01 - 8.7; p <0.05). In those proceeding to implantation there was no difference in 10mTW at 1 year (ANOVA (F(3,24) = 2.6, p=0.13). Currently, 15 (75%) remain ambulatory (mean 3.75 years, range 1-9). After implant, 17 (85%) discontinued all oral anti-spasticity treatments conferring other benefits. CONCLUSION: Ambulation in people with MS can be preserved for several years whilst effectively treating spasticity with ITB with careful patient selection; ITB should not be considered a last resort.

Neonatal organ donation: Ethical insights and policy implications.

In the realm of clinical ethics as well as in health policy and organizational ethics, the onus of our work as ethicists is to optimize the medical care and experience of the patient to better target ethical dilemmas that develop in the course of care delivery. The role of ethics is critical in all aspects of medicine, but particularly so in the difficult and often challenging cases that arise in the care of pregnant women and newborns. One exemplary situation is that when a pregnant woman and her partner consider neonatal organ donation after receiving news of a terminal diagnosis and expected death of the newborn. While a newer, less practiced form of organ donation, this approach is gaining greater visibility as an option for parents facing this terminal outcome. The aim of our paper is to highlight some of the key ethical issues associated with neonatal organ donation and identify clinical and logistical aspects of implementing such an approach to facilitate organ donation.

Soil formate regulates the fungal nitrous oxide emission pathway.

Fungal activity is a major driver in the global nitrogen cycle, and mounting evidence suggests that fungal denitrification activity contributes significantly to soil emissions of the greenhouse gas nitrous oxide (N(2)O). The metabolic pathway and oxygen requirement for fungal denitrification are different from those for bacterial denitrification. We hypothesized that the soil N(2)O emission from fungi is formate and O(2) dependent and that land use and landforms could influence the proportion of N(2)O coming from fungi. Using substrate-induced respiration inhibition under anaerobic and aerobic conditions in combination with (15)N gas analysis, we found that formate and hypoxia (versus anaerobiosis) were essential for the fungal reduction of (15)N-labeled nitrate to (15)N(2)O. As much as 65% of soil-emitted N(2)O was attributable to fungi; however, this was found only in soils from water-accumulating landforms. From these results, we hypothesize that plant root exudates could affect N(2)O production from fungi via the proposed formate-dependent pathway.

Identification of SLF1 as a new copper homeostasis gene involved in copper sulfide mineralization in Saccharomyces cerevisiae.

In Saccharomyces cerevisiae, at least 12 genes are important for cells to propagate in medium containing elevated concentrations of copper salts (J. Welch, S. Fogel, C. Buchman, and M. Karin, EMBO J. 8:255-260, 1989). Complementation studies were carried out on a copper-sensitive mutation (cup14) from this group. A new yeast gene, designated SLF1, was identified as a multicopy suppressor of the cup14 mutation. Slf1 is important for the physiological process of copper sulfide (CuS) mineralization on the surface of cells cultured in medium containing copper salts. CuS mineralization causes the cells to turn brown. Disruption of SLF1, which is located close to the telomere region of chromosome IV, leads to limited copper sensitivity, and the resulting cells lack the normal brownish coloration when grown in CuSO4-containing medium. Overproduction of Slf1 in wild-type cells confers superresistance to CuSO4 and enhances the coloration of cells cultured in the presence of CuSO4. Upon addition of KCN to Cu-grown cells, the brownish coloration was bleached instantly, and copper ions were solubilized. These data are consistent with Slf1-dependent accumulation of CuS complexes on the cell surface. Disruption of SFL1 also results in loss of the ability of yeast cells to deplete Cu but not Cd ions from the growth medium, whereas overexpression enhances Ca depletion ability and the resulting deposition of CuS particles. It is proposed that Slfl participates in a copper homeostasis pathway, distinct from the Cup1 detoxification system, that leads to sulfide generation and CuS biomineralization on the cell surface. This process may coordinate with the Cup1 pathway at different copper concentrations to prevent copper-induced toxicity.

A hybrid polymer gel with controlled rates of cross-link rupture and self-repair.

A family of hybrid polymer gels is described, in which covalent cross-links create a permanent, stiff scaffold onto which reversible metal-ligand coordinative cross-links are added. The reversible metal-ligand interactions are shown to bear mechanical stress within the hybrid gel, and relaxations in response to that applied stress are consistent with the stress-free kinetics of ligand exchange in systems that model the reversible cross-links. The stress-induced dissociation of a model metal-ligand complex is examined by a single-molecule force spectroscopy, and its mechanical response is compared with a previously studied complex. The mechanical response of the individual interactions is relevant to those found in the family of hybrid gels, and the modular platform is therefore suitable for the study of stress-induced molecular dissociations, and their subsequent repair, within a macroscopic material of fixed structure.

Combination of infliximab with thiopurines significantly reduces white cell and neutrophil counts in inflammatory bowel disease patients.

BACKGROUND: The effects of thiopurines on white cell count are well documented. OBJECTIVE: We compared the effects of infliximab 5 mg/kg monotherapy and combination of infliximab with thiopurines on the total and differential white cell count (WBC). METHODS: 13 IBD patients treated with infliximab monotherapy and 18 IBD patients treated with a combination of infliximab and thiopurines were included in the study. Using retrospective data, cell counts were examined prior to induction of infliximab, and at 6 weeks and 1 year post-induction. RESULTS: The patients on combination therapy had an absolute WBC at 52 weeks of 5.7 whereas that of patients on Infliximab monotherapy at the same time point was 8.3 with comparable neutrophil count of 3.4 and 5.4. The results showed a significant reduction in white cell count and neutrophils at 6 weeks which persisted at 52 weeks in both groups (p < 0.05) with a greater drop in patients on combination infliximab and thiopurine (p < 0.05) as compared to Infliximab monotherapy. There was no significant change in the lymphocyte count. CONCLUSION: Full blood counts should be closely monitored in all patients starting infliximab therapy, in particular patients receiving concomitant thiopurines.

Simple keel fixation technique for endoscopic repair of anterior glottic stenosis.

The use of keels in the treatment of anterior glottic stenosis is well established. A variety of methods for keel fixation have previously been documented. We describe a simple technique of securing a Silastic keel, placed endoscopically, with a simple percutaneous suture, after laser vaporization of an anterior commissure web.