Neural stem cell delivery of an oncolytic adenovirus in newly diagnosed malignant glioma: a first-in-human, phase 1, dose-escalation trial.

BACKGROUND: Malignant glioma is the most common and lethal primary brain tumour, with dismal survival rates and no effective treatment. We examined the safety and activity of NSC-CRAd-S-pk7, an engineered oncolytic adenovirus delivered by neural stem cells (NSCs), in patients with newly diagnosed high-grade glioma. METHODS: This was a first-in-human, open-label, phase 1, dose-escalation trial done to determine the maximal tolerated dose of NSC-CRAd-S-pk7, following a 3 + 3 design. Patients with newly diagnosed, histologically confirmed, high-grade gliomas (WHO grade III or IV) were recruited. After neurosurgical resection, NSC-CRAd-S-pk7 was injected into the walls of the resection cavity. The first patient cohort received a dose starting at 6·25 × 1010 viral particles administered by 5·00 × 107 NSCs, the second cohort a dose of 1·25 × 1011 viral particles administered by 1·00 × 108 NSCs, and the third cohort a dose of 1·875 × 1011 viral particles administered by 1·50 × 108 NSCs. No further dose escalation was planned. Within 10-14 days, treatment with temozolomide and radiotherapy was initiated. Primary endpoints were safety and toxicity profile and the maximum tolerated dose for a future phase 2 trial. All analyses were done in all patients who were included in the trial and received the study treatment and were not excluded from the study. Recruitment is complete and the trial is finished. The trial is registered with ClinicalTrials.gov, NCT03072134. FINDINGS: Between April 24, 2017, and Nov 13, 2019, 12 patients with newly diagnosed, malignant gliomas were recruited and included in the safety analysis. Histopathological evaluation identified 11 (92%) of 12 patients with glioblastoma and one (8%) of 12 patients with anaplastic astrocytoma. The median follow-up was 18 months (IQR 14-22). One patient receiving 1·50 × 108 NSCs loading 1·875 × 1011 viral particles developed viral meningitis (grade 3) due to the inadvertent injection of NSC-CRAd-S-pk7 into the lateral ventricle. Otherwise, treatment was safe as no formal dose-limiting toxicity was reached, so 1·50 × 108 NSCs loading 1·875 × 1011 viral particles was recommended as a phase 2 trial dose. There were no treatment-related deaths. The median progression-free survival was 9·1 months (95% CI 8·5-not reached) and median overall survival was 18·4 months (15·7-not reached). INTERPRETATION: NSC-CRAd-S-pk7 treatment was feasible and safe. Our immunological and histopathological findings support continued investigation of NSC-CRAd-S-pk7 in a phase 2/3 clinical trial. FUNDING: US National Institutes of Health.

A first-in-human phase 0 clinical study of RNA interference-based spherical nucleic acids in patients with recurrent glioblastoma.

Glioblastoma (GBM) is one of the most difficult cancers to effectively treat, in part because of the lack of precision therapies and limited therapeutic access to intracranial tumor sites due to the presence of the blood-brain and blood-tumor barriers. We have developed a precision medicine approach for GBM treatment that involves the use of brain-penetrant RNA interference-based spherical nucleic acids (SNAs), which consist of gold nanoparticle cores covalently conjugated with radially oriented and densely packed small interfering RNA (siRNA) oligonucleotides. On the basis of previous preclinical evaluation, we conducted toxicology and toxicokinetic studies in nonhuman primates and a single-arm, open-label phase 0 first-in-human trial (NCT03020017) to determine safety, pharmacokinetics, intratumoral accumulation and gene-suppressive activity of systemically administered SNAs carrying siRNA specific for the GBM oncogene Bcl2Like12 (Bcl2L12). Patients with recurrent GBM were treated with intravenous administration of siBcl2L12-SNAs (drug moniker: NU-0129), at a dose corresponding to 1/50th of the no-observed-adverse-event level, followed by tumor resection. Safety assessment revealed no grade 4 or 5 treatment-related toxicities. Inductively coupled plasma mass spectrometry, x-ray fluorescence microscopy, and silver staining of resected GBM tissue demonstrated that intravenously administered SNAs reached patient tumors, with gold enrichment observed in the tumor-associated endothelium, macrophages, and tumor cells. NU-0129 uptake into glioma cells correlated with a reduction in tumor-associated Bcl2L12 protein expression, as indicated by comparison of matched primary tumor and NU-0129-treated recurrent tumor. Our results establish SNA nanoconjugates as a potential brain-penetrant precision medicine approach for the systemic treatment of GBM.

Report of the Key Opinion Leaders Meeting on Stem Cell-derived Beta Cells.

Beta cell replacement has the potential to restore euglycemia in patients with insulin-dependent diabetes. Although great progress has been made in establishing allogeneic islet transplantation from deceased donors as the standard of care for those with the most labile diabetes, it is also clear that the deceased donor organ supply cannot possibly treat all those who could benefit from restoration of a normal beta cell mass, especially if immunosuppression were not required. Against this background, the International Pancreas and Islet Transplant Association in collaboration with the Harvard Stem Cell Institute, the Juvenile Diabetes Research Foundation (JDRF), and the Helmsley Foundation held a 2-day Key Opinion Leaders Meeting in Boston in 2016 to bring together experts in generating and transplanting beta cells derived from stem cells. The following summary highlights current technology, recent significant breakthroughs, unmet needs and roadblocks to stem cell-derived beta cell therapies, with the aim of spurring future preclinical collaborative investigations and progress toward the clinical application of stem cell-derived beta cells.

UK FASHIoN: feasibility study of a randomised controlled trial of arthroscopic surgery for hip impingement compared with best conservative care.

BACKGROUND: Femoroacetabular impingement (FAI) is a syndrome of hip or groin pain associated with shape abnormalities of the hip joint. Treatments include arthroscopic surgery and conservative care. This study explored the feasibility of a randomised controlled trial to compare these treatments. OBJECTIVES: The objectives of this study were to estimate the number of patients available for a full randomised controlled trial (RCT); to explore clinician and patient willingness to participate in such a RCT; to develop consensus on eligibility criteria, surgical and best conservative care protocols; to examine possible outcome measures and estimate the sample size for a full RCT; and to develop trial procedures and estimate recruitment and follow-up rates. METHODS: Pre-pilot work: we surveyed all UK NHS hospital trusts (n = 197) to identify all FAI surgeons and to estimate how much arthroscopic FAI surgery they performed. We interviewed a purposive sample of 18 patients, 36 physiotherapists, 18 surgeons and two sports physicians to explore attitudes towards a RCT and used consensus-building methods among them to develop treatment protocols and patient information. Pilot RCT: we performed a pilot RCT in 10 hospital trusts. Patients were randomised to receive either hip arthroscopy or best conservative care and then followed up at 3, 6 and 12 months using patient-reported questionnaires for hip pain and function, activity level, quality of life, and a resource-use questionnaire. Qualitative recruitment intervention: we performed semistructured interviews with all researchers and clinicians involved in the pilot RCT in eight hospital trusts and recorded and analysed diagnostic and recruitment consultations with eligible patients. RESULTS: We identified 120 surgeons who reported treating at least 1908 patients with FAI by hip arthroscopy in the NHS in the financial year 2011/12. There were 34 hospital trusts that performed ≥ 20 arthroscopic FAI operations in the year. We found that clinicians were positive about a RCT: only half reported equipoise, but most said that they would be prepared to randomise patients. Patients strongly supported a RCT, but expressed concerns about its design; these were used to develop patient information for the pilot RCT. We developed a surgical protocol and showed that this could be used in a RCT. We developed a physiotherapy-led exercise-based package of best conservative care called 'personalised hip therapy' and showed that this was practicable. In the pilot RCT, we recruited 42 out of 60 eligible patients (70%) across nine sites. The mean duration and recruitment rate across all sites were 4.5 months and one patient per site per month, respectively. The lead site recruited for the longest period (9.3 months) and accrued the largest number of patients (2.1 patients per month). We recorded and analysed 84 diagnostic and recruitment consultations in 60 patients and used these to develop a model for an optimal recruitment consultation. We identified the International Hip Outcome Tool at 12 months as an appropriate outcome measure and estimated the sample size for a full trial as 344 participants: a number that could be recruited in 25 centres over 18 months. CONCLUSION: We have demonstrated that it is feasible to perform a RCT to establish the clinical effectiveness of hip arthroscopy compared with best conservative care for FAI. We have designed a full trial and developed and tested procedures for it, including an innovative approach to recruitment. We propose that a full trial be implemented. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Talking about smoking in primary care medical practice--results of experimental studies from the US, UK and Germany.

OBJECTIVE: To analyse effects of patient and physician characteristics on questions and advice about smoking in primary care practice and to examine country differences. METHODS: We conducted a factorial experiment, employing filmed scenarios in which actors played the role of patients with symptoms of coronary heart disease (CHD) or type 2 diabetes. Versions were filmed with patient-actors of different gender, age, race, and socioeconomic status. The videotapes were presented to primary care physicians in the US, UK and Germany. Physicians were asked whether they would ask questions about smoking or give cessation advice. RESULTS: Female and older CHD patients are less likely to be asked or get advice about smoking in all three countries. Effects of physician attributes are weak and inconsistent. Compared to physicians in the US and the UK, German doctors are least likely to ask questions or give advice. CONCLUSIONS: Although all physicians viewed the same cases their questioning and advice giving differed according to patient attributes and country. Due to the experimental design external validity of the study may be limited. PRACTICE IMPLICATIONS: Findings have implications for medical education and professional training of physicians as well as for the organization and financing of health care.

Influence of patient characteristics on doctors' questioning and lifestyle advice for coronary heart disease: a UK/US video experiment.

BACKGROUND: Risk factors for coronary heart disease (CHD) vary with patient characteristics but we do not know how this influences doctors' questioning and advice giving. AIMS: To find out whether four patient characteristics - age (55 versus 75 years), sex, class, and race - influence primary care doctors' questioning style and advice giving in the United Kingdom (UK) and United States (US). DESIGN OF STUDY: A factorial experiment using video simulation of a patient consulting with CHD symptoms, designed to systematically alter their age, sex, class, and race. SETTING: Surrey, south east London and the West Midlands in the UK, and Massachusetts in the US. METHOD: A stratified random sample of 128 general practitioners (GPs) in the UK and 128 primary care doctors in the US were shown video vignettes in their practices of patient consultations, and interviewed about patient management strategies. RESULTS: Sex and age influence doctors' questioning of patients presenting with CHD. Men are asked more questions overall, particularly about smoking and drinking. Middle-aged patients are asked more about their lifestyle. Advice about smoking is given to more men than women, and to more mid-life than older patients. Women doctors question patients about their lifestyle more often, and give more advice to patients about their diet. CONCLUSION: Doctors' questioning strategies are influenced by patients' sex and age, suggesting that doctors may miss smoking- and alcohol-related factors among women and older patients with CHD. Doctors give more advice about smoking to men, despite sex equality in smoking prevalence. Therefore, doctors' information seeking and advice giving do not match known patient risk factors.

Do clinical nurse specialists in palliative care de-skill or empower general ward nurses?

This article reports on a small-scale exploratory study looking into the relationships between specialist nurses and general nurses in acute palliative care, to establish mutual role expectations and conditions under which generalists exhibit empowered or de-skilled behaviour. The main aims were to investigate understandings of role expectation and to establish the conditions under which generalists exhibited empowered or de-skilled behaviour. Semi-structured interviews, based on a patient vignette, were conducted with eight general nurses and two specialist nurses in one UK NHS trust. It was found that generalists valued specialists' clinical knowledge and skills, especially their communication skills. However, generalists demonstrated little insight into the work methods or full job remit, particularly the educational role, of specialists. There was a common understanding of the generalist's role by both generalists and specialists. Generalists shared anxieties about palliative care. De-skilling was not reported, but generalists acknowledge 'handing over' care and a disinclination to develop challenging clinical skills. Empowerment was not found to be associated with clinical grade, but with motivation to learn about palliative care. Further research is required to verify these preliminary findings.

Clinical predictors of cervical intraepithelial neoplasia 2 or greater in women with mildly abnormal Pap smears.

OBJECTIVE: To evaluate clinical predictors of cervical intraepithelial neoplasia (CIN) 2 or greater in women with mildly abnormal Pap smears. STUDY DESIGN: Using a computerized colposcopy database of 2,200 women, we identified 1,494 with atypical squamous cells of undetermined significance (ASCUS) or low grade squamous intraepithelial lesions (LSILs). Of the 1,494, 1,016 (68%) underwent biopsy and formed the cohort for this retrospective review. Clinical variables associated with CIN 2 or greater in a univariate analysis (P < .10) were included in a multivariate regression analysis. RESULTS: Of the 1,016 women biopsied, 195 (19%) had CIN 2 or greater. In the initial analysis, age (< 35 years), race (Caucasian and African American), marital status (unmarried) and smoking status (current and former) were found to be significantly associated with more severe histologic disease. In the regression analysis, a history of smoking remained a statistically significant clinical predictor of CIN 2 or greater (odds ratio 1.57, 95% confidence intervals 1.09-2.27). CONCLUSION: A significant predictor of CIN 2 or greater in a large cohort of women with mildly abnormal Pap smears was a history of current or former smoking.