A nanoengineered topical transmucosal cisplatin delivery system induces anti-tumor response in animal models and patients with oral cancer.

Despite therapeutic advancements, oral cavity squamous cell carcinoma (OCSCC) remains a difficult disease to treat. Systemic platinum-based chemotherapy often leads to dose-limiting toxicity (DLT), affecting quality of life. PRV111 is a nanotechnology-based system for local delivery of cisplatin loaded chitosan particles, that penetrate tumor tissue and lymphatic channels while avoiding systemic circulation and toxicity. Here we evaluate PRV111 using animal models of oral cancer, followed by a clinical trial in patients with OCSCC. In vivo, PRV111 results in elevated cisplatin retention in tumors and negligible systemic levels, compared to the intravenous, intraperitoneal or intratumoral delivery. Furthermore, PRV111 produces robust anti-tumor responses in subcutaneous and orthotopic cancer models and results in complete regression of carcinogen-induced premalignant lesions. In a phase 1/2, open-label, single-arm trial (NCT03502148), primary endpoints of efficacy (≥30% tumor volume reduction) and safety (incidence of DLTs) of neoadjuvant PRV111 were reached, with 69% tumor reduction in ~7 days and over 87% response rate. Secondary endpoints (cisplatin biodistribution, loco-regional control, and technical success) were achieved. No DLTs or drug-related serious adverse events were reported. No locoregional recurrences were evident in 6 months. Integration of PRV111 with current standard of care may improve health outcomes and survival of patients with OCSCC.

Characterization and Associated Costs of Constipation Relating to Exposure to Strong Opioids in England: An Observational Study.

PURPOSE: Opioid use is associated with gastrointestinal adverse events, including nausea and constipation. We used a real-world dataset to characterize the health care burden associated with opioid-induced constipation (OIC) with particular emphasis on strong opioids. METHODS: This retrospective cohort study was conducted using the Clinical Practice Research Datalink, a large UK primary care dataset linked to hospital data. Patients prescribed opioids during 2016 were selected and episodes of opioid therapy constructed. Episodes with ≥84 days of exposure were classified as chronic, with date of first prescription as the index date. The main analysis focused on patients prescribed strong opioids who were laxative naive. Constipation was defined by ≥2 laxative prescriptions during the opioid episode. Patients for whom initial laxative therapy escalated by switch, augmentation, or dose were defined as OIC unstable, and the first 3 lines of OIC escalation were classified. Health care costs accrued in the first 12 months of the opioid episode were aggregated and compared. FINDINGS: A total of 27,629 opioid episodes were identified; 5916 (21.4%) involved a strong opioid for patients who were previously laxative naive. Of these patients, 2886 (48.8%) were defined as the OIC population; 941 (33.26%) were classified as stable. Of the 1945 (67.4%) episodes classified as unstable, 849 (43.7%), 360 (18.5%), and 736 (37.8%) had 1, 2, and ≥3 changes of laxative prescription, respectively. Patients without OIC had lower costs per patient year (£3822 [US$5160/€4242]) compared with OIC (£4786 [US$6461/€5312]). Costs increased as patients had multiple changes in therapy: £4696 (US$6340/€5213), £4749 (US$6411/€5271), and £4981 (US$6724/€5529) for 1, 2, and ≥3 changes, respectively. The adjusted cost ratio relative to non-OIC was 1.14 (95% CI, 1.09-1.32) for those classified as stable and 1.19 (95% CI, 1.09-1.32) for those with ≥3 laxative changes. Similar patterns were observed for patients taking anyopioid, with costs increased for those classified as having OIC (£3727 [US$5031/€4137] vs £2379 [US$3212 /€2641),and for those patients classified as unstable versus stable (£3931 [US$5307/€4363] vs £3432 [US$4633/€3810). Costs increased with each additional line of therapy from £3701 (US$4996/€4108), £3916 (US$5287/€4347), and £4318 (US$5829/€4793). IMPLICATIONS: OIC was a common adverse event of opioid treatment and was poorly controlled for a large number of patients. Poor control was associated with increased health care costs. The impact of OIC should be considered when prescribing opioids. These results should be interpreted with consideration of the caveats associated with the analysis of routine data.

Metabolic engineering of Clostridium thermocellum for n-butanol production from cellulose.

BACKGROUND: Biofuel production from plant cell walls offers the potential for sustainable and economically attractive alternatives to petroleum-based products. In particular, Clostridium thermocellum is a promising host for consolidated bioprocessing (CBP) because of its strong native ability to ferment cellulose. RESULTS: We tested 12 different enzyme combinations to identify an n-butanol pathway with high titer and thermostability in C. thermocellum. The best producing strain contained the thiolase-hydroxybutyryl-CoA dehydrogenase-crotonase (Thl-Hbd-Crt) module from Thermoanaerobacter thermosaccharolyticum, the trans-enoyl-CoA reductase (Ter) enzyme from Spirochaeta thermophila and the butyraldehyde dehydrogenase and alcohol dehydrogenase (Bad-Bdh) module from Thermoanaerobacter sp. X514 and was able to produce 88 mg/L n-butanol. The key enzymes from this combination were further optimized by protein engineering. The Thl enzyme was engineered by introducing homologous mutations previously identified in Clostridium acetobutylicum. The Hbd and Ter enzymes were engineered for changes in cofactor specificity using the CSR-SALAD algorithm to guide the selection of mutations. The cofactor engineering of Hbd had the unexpected side effect of also increasing activity by 50-fold. CONCLUSIONS: Here we report engineering C. thermocellum to produce n-butanol. Our initial pathway designs resulted in low levels (88 mg/L) of n-butanol production. By engineering the protein sequence of key enzymes in the pathway, we increased the n-butanol titer by 2.2-fold. We further increased n-butanol production by adding ethanol to the growth media. By combining all these improvements, the engineered strain was able to produce 357 mg/L of n-butanol from cellulose within 120 h.

Natural History of Patients Taking Rifaximin-α for Recurrent Hepatic Encephalopathy and Risk of Future Overt Episodes and Mortality: A Post-hoc Analysis of Clinical Trials Data.

PURPOSE: Hepatic encephalopathy (HE) is a complication of cirrhosis signaling decompensation and is associated with mortality. There has been little characterization of HE once an incident episode has occurred and of what effect the transition to overt HE might have on outcomes. We characterized the relationships between the number of previous HE episodes and risk of subsequent episodes and mortality to better understand the natural history of HE. METHODS: Data on 321 patients from a 24-month, open-label, nonrandomized trial evaluating the long-term safety profile and tolerability of twice-daily rifaximin-α 550 mg were analyzed. Patients were followed for a mean of 1.5 years (total follow-up of 467 years). FINDINGS: There were a total of 334 HE episodes and 75 deaths, corresponding to unadjusted event rates of 715 HE episodes and 161 deaths per 1000 years. There was a direct association between rate of subsequent HE episodes and number of prior HE episodes; the risk of subsequent HE episodes was elevated for each additional HE episode (hazard ratio = 1.23; 95% CI, 1.19-1.29). There was a nonlinear, nonmonotonic relationship between risk of death and number of prior HE episodes; risk initially increased, then decreased, and finally plateaued as the number of prior HE episodes increased. IMPLICATIONS: Patients with a larger number of previous, overt HE episodes had a greater risk for subsequent episodes. However, mortality risk decreased after the third episode of HE. A plausible hypothesis to explain this finding is that risk of mortality may be reduced in patients receiving long-term rifaximin-α therapy.

Considerations and preliminary proposals for defining a reference case for economic evaluations in ankylosing spondylitis.

Since healthcare resources are scarce, choices have to be made on how they will be allocated. The use of economic evaluations using cost-effectiveness analyses has increased rapidly as policymakers have realized their value in maximizing the population's benefits (in terms of length of life and health status) within a given budget. Following efforts by OMERACT to create reference case definitions for the conduct of economic evaluation in rheumatoid arthritis, osteoporosis, and osteoarthritis, we review various methodological areas and research decisions that could benefit from a consensus between researchers, clinicians, and drug developers in terms of an ankylosing spondylitis (AS) reference case. Ten methodological issues are presented that will be important for future development of evaluations. Tentative proposals to define the issues in a reference case for AS are made, along with recommendations for further research.

A cost-utility analysis of low-dose hormone replacement therapy in postmenopausal women with an intact uterus.

OBJECTIVE: The objective of this study was to evaluate the cost utility of one year's treatment with a low-dose conjugated estrogen/medroxyprogesterone acetate (CE/MPA low dose) preparation (Premique Low Dose [Wyeth Pharmaceuticals, Maidenhead, UK]), compared with a higher-dose preparation (Premique; CE/MPA [Wyeth Pharmaceuticals, Maidenhead, UK]), in postmenopausal women with an intact uterus. The evaluation captured the resource implications associated with the difference in treatment discontinuation and adverse event driven consultations in patients receiving either the low- or higher-dose preparation. This economic evaluation was conducted from the perspective of the NHS. RESEARCH DESIGN AND METHODS: A health economic model was developed to calculate the incremental cost per quality-adjusted life year (QALY) gained from treatment with a lower-dose CE/MPA combination, compared with a higher-dose CE/MPA preparation. Cohorts of 100 patients were assumed to receive either CE/MPA low dose or CE/MPA for one year. A probabilistic sensitivity analysis was used to explore whether the base case model was robust to the assumptions employed. Neither costs nor consequences were discounted because of the one year timeframe. RESULTS: In the base case, CE/MPA low dose dominates, i.e. it showed a greater health gain at a reduced cost, in both mild and severe symptom populations. These results were repeated in the sensitivity analysis, with the cost-effectiveness planes for both mild and severe symptom populations showing a greater utility at a reduced cost. CONCLUSIONS: CE/MPA low dose has been demonstrated to be a cost-effective treatment of estrogen-deficiency symptoms in postmenopausal women with an intact uterus. It has great potential for increasing the number of patients benefiting from relief of menopausal symptoms while also reducing the resource utilisation associated with managing the adverse effects associated with higher-dose HRT.

The cost-burden of paediatric pneumococcal disease in the UK and the potential cost-effectiveness of prevention using 7-valent pneumococcal conjugate vaccine.

We modelled the epidemiology and cost of pneumococcal disease in children in the UK and the cost-effectiveness of immunisation with 7-valent pneumococcal conjugate vaccine (PCV). We estimated the incidence of pneumococcal meningitis, pneumococcal septicaemia, all-cause pneumonia and all-cause otitis media (OM). We further estimated the impact of vaccination with associated costs and outcomes. Vaccine cost was pound 39.25 per dose with a pound 10 administration cost; vaccination schedule and efficacy were taken from a recent trial. We estimated that in each UK annual birth cohort there are 881,146 episodes of these infections and 149 deaths associated with pneumococcal meningitis, pneumococcal septicaemia or all-cause pneumonia and that PCV would prevent 54,384 episodes and 29 deaths. NHS cost per life year gained was estimated at pound 31,512, close to the limit at which PCV would be considered cost-effective.