Tumor volumes in T3 supraglottic cancers treated with radiotherapy in the modern era: A study of the Canadian Head & Neck Collaborative Research Initiative.

PURPOSE: To evaluate the association of primary tumor volume (TV) with overall survival (OS) and disease-free survival (DFS) in T3 N0-3M0 supraglottic cancers treated with intensity-modulated radiotherapy (IMRT). METHODS: This was a retrospective cohort study involving 239 patients diagnosed with T3 N0-3M0 supraglottic cancers between 2002 and 2018 from seven regional cancer centers in Canada. Clinical data were obtained from the patient records. Supraglottic TV was measured by neuroradiologists on diagnostic imaging. Kaplan-Meier method was used for survival probabilities, and a restricted cubic spline Cox proportional hazards regression analysis was used to analyze TV associations with OS and DFS. RESULTS: Mean (SD) of participants was 65.2 (9.4) years; 176 (73.6%) participants were male. 90 (38%) were N0, and 151 (64%) received concurrent systemic therapy. Mean TV (SD) was 11.37 (12.11) cm3 . With mean follow up (SD) of 3.28 (2.60) years, 2-year OS was 72.7% (95% CI 66.9%-78.9%) and DFS was 53.6% (47.4%-60.6%). Increasing TV was associated (per cm3 increase) with worse OS (HR, 1.01, 95% CI 1.00-1.02, p < 0.01) and DFS (HR, 1.01, 95% CI 1.00-1.02, p = 0.02). CONCLUSIONS: Increasing primary tumor volume is associated with worse OS and DFS in T3 supraglottic cancers treated with IMRT, with no clear threshold. The findings suggest that patients with larger tumors and poor baseline laryngeal function may benefit from upfront laryngectomy with adjuvant radiotherapy.

Association of Primary Tumor Volume With Survival in Patients With T3 Glottic Cancer Treated With Radiotherapy: A Study of the Canadian Head & Neck Collaborative Research Initiative.

Importance: The association of primary tumor volume with outcomes in T3 glottic cancers treated with radiotherapy with concurrent chemotherapy remains unclear, with some evidence suggesting worse locoregional control in larger tumors. Objective: To evaluate the association of primary tumor volume with oncologic outcomes in patients with T3 N0-N3 M0 glottic cancer treated with primary (chemo)radiotherapy in a large multi-institutional study. Design, Setting, and Participants: This multi-institutional retrospective cohort study involved 7 Canadian cancer centers from 2002 to 2018. Tumor volume was measured by expert neuroradiologists on diagnostic imaging. Clinical and outcome data were extracted from electronic medical records. Overall survival (OS) and disease-free survival (DFS) outcomes were assessed with marginal Cox regression. Laryngectomy-free survival (LFS) was modeled as a secondary analysis. Patients diagnosed with cT3 N0-N3 M0 glottic cancers from 2002 to 2018 and treated with curative intent intensity-modulated radiotherapy (IMRT) with or without chemotherapy. Overall, 319 patients met study inclusion criteria. Exposures: Tumor volume as measured on diagnostic imaging by expert neuroradiologists. Main Outcomes and Measures: Primary outcomes were OS and DFS; LFS was assessed as a secondary analysis, and late toxic effects as an exploratory analysis determined before start of the study. Results: The mean (SD) age of participants was 66 (12) years and 279 (88%) were men. Overall, 268 patients (84%) had N0 disease, and 150 (47%) received concurrent systemic therapy. The mean (SD) tumor volume was 4.04 (3.92) cm3. With a mean (SD) follow-up of 3.85 (3.04) years, there were 91 (29%) local, 35 (11%) regional, and 38 (12%) distant failures. Increasing tumor volume (per 1-cm3 increase) was associated with significantly worse adjusted OS (hazard ratio [HR], 1.07; 95% CI, 1.03-1.11) and DFS (HR, 1.04; 95% CI, 1.01-1.07). A total of 62 patients (19%) underwent laryngectomies with 54 (87%) of these within 800 days after treatment. Concurrent systemic therapy was associated with improved LFS (subdistribution HR, 0.63; 95% CI, 0.53-0.76). Conclusions and Relevance: Increasing tumor volumes in cT3 glottic cancers was associated with worse OS and DFS, and systemic therapy was associated with improved LFS. In absence of randomized clinical trial evidence, patients with poor pretreatment laryngeal function or those ineligible for systemic therapy may be considered for primary surgical resection with postoperative radiotherapy.

Development of a Microgram Scale Video-Microscopic Method to Investigate Dissolution Behavior of Poorly Water-Soluble Drugs.

Poor aqueous solubility is a common characteristic of new drug candidates, which leads to low or inconsistent oral bioavailability. This has sparked an interest in material efficient testing of solubility and dissolution rate. The aim was to develop a microgram scale video-microscopic method to screen the dissolution rates of poorly water-soluble drugs. This method was applied to six drugs (carvedilol, diazepam, dipyridamole, felodipine, fenofibrate, and indomethacin) in fasted state simulated intestinal fluid (FaSSIF), of indomethacin in buffer with varying pH, and of diazepam and dipyridamole in customized media. An additional aim was to track phase transformations for carbamazepine in FaSSIF. The dissolution rates and particle behavior of the drugs were investigated by tracking particle surface area over time using optical video-microscopy. Applying miniaturized UV spectroscopic dissolution resulted in a similar grouping of dissolution rates and pH effects, as for the video-microscopic setup. Using customized media showed that lysophospholipid enhanced the dissolution rate of diazepam and dipyridamole. The video-microscopic setup allowed for the nucleation of transparent particles on dissolving carbamazepine particles to be tracked over time. The developed setup offers a material efficient screening approach to group drugs according to dissolution rate, where the use of optical microscopy helps to achieve a high sample throughput.

An interlaboratory investigation of intrinsic dissolution rate determination using surface dissolution.

The purpose of this study was to conduct an interlaboratory ring-study, with six partners (academic and industrial), investigating the measurement of intrinsic dissolution rate (IDR) using surface dissolution imaging (SDI) equipment. Measurement of IDR is important in pharmaceutical research as it provides characterising information on drugs and their formulations. This work allowed us to assess the SDI's interlaboratory performance for measuring IDR using a defined standard operating procedure (see supporting information) and six drugs assigned as low (tadalafil, bromocriptine mesylate), medium (carvedilol, indomethacin) and high (ibuprofen, valsartan) solubility compounds. Fasted State Simulated Intestinal Fluid (FaSSIF) and blank FaSSIF (without sodium taurocholate and lecithin) (pH 6.5) were used as media. Using the standardised protocol an IDR value was obtained for all compounds and the results show that the overall IDR rank order matched the solubility rank order. Interlaboratory variability was also examined and it was observed that the variability for lower solubility compounds was higher, coefficient of variation >50%, than for intermediate and high solubility compounds, with the exception of indomethacin in FaSSIF medium. Inter laboratory variability is a useful descriptor for understanding the robustness of the protocol and the system variability. On comparison to another published small-scale IDR study the rank ordering with respect to dissolution rate is identical except for the high solubility compounds. This results indicates that the SDI robustly measures IDR however, no recommendation on the use of one small scale method over the other is made.

Biorelevant intrinsic dissolution profiling in early drug development: Fundamental, methodological, and industrial aspects.

Intrinsic dissolution rate (IDR) is the surface specific dissolution rate of a drug. In early drug development, this property (among other parameters) is measured in order to compare different polymorphs and salt forms, guide formulation decisions, and to provide a quality marker of the active pharmaceutical ingredient (API) during production. In this review, an update on different methods and small-scale techniques that have recently evolved for determination of IDR is provided. The importance of biorelevant media and the hydrodynamic conditions of dissolution are also discussed. Different preparation techniques for samples are presented with a focus on disc, particle- and crystal-based methods. A number of small-scale techniques are then described in detail, and their applicability domains are identified. Finally, an updated industrial perspective is provided about IDR's place in the early drug development process.

High carnivore population density highlights the conservation value of industrialised sites.

As the environment becomes increasingly altered by human development, the importance of understanding the ways in which wildlife interact with modified landscapes is becoming clear. Areas such as industrial sites are sometimes presumed to have little conservation value, but many of these sites have areas of less disturbed habitats around their core infrastructure, which could provide ideal conditions to support some species, such as mesocarnivores. We conducted the first assessments of the density of serval (Leptailurus serval) at the Secunda Synfuels Operations plant, South Africa, using camera trap surveys analysed within a spatially explicit capture recapture framework. We show that servals occurred at densities of 76.20-101.21 animals per 100 km², which are higher than previously recorded densities for this species, presumably due to high abundance of prey and the absence of persecution and/or competitor species. Our findings highlight the significant conservation potential of industrialised sites, and we suggest that such sites could help contribute towards meeting conservation goals.

Investigation of the Intra- and Interlaboratory Reproducibility of a Small Scale Standardized Supersaturation and Precipitation Method.

The high number of poorly water-soluble compounds in drug development has increased the need for enabling formulations to improve oral bioavailability. One frequently applied approach is to induce supersaturation at the absorptive site, e.g., the small intestine, increasing the amount of dissolved compound available for absorption. However, due to the stochastic nature of nucleation, supersaturating drug delivery systems may lead to inter- and intrapersonal variability. The ability to define a feasible range with respect to the supersaturation level is a crucial factor for a successful formulation. Therefore, an in vitro method is needed, from where the ability of a compound to supersaturate can be defined in a reproducible way. Hence, this study investigates the reproducibility of an in vitro small scale standardized supersaturation and precipitation method (SSPM). First an intralaboratory reproducibility study of felodipine was conducted, after which seven partners contributed with data for three model compounds; aprepitant, felodipine, and fenofibrate, to determine the interlaboratory reproducibility of the SSPM. The first part of the SSPM determines the apparent degrees of supersaturation (aDS) to investigate for each compound. Each partner independently determined the maximum possible aDS and induced 100, 87.5, 75, and 50% of their determined maximum possible aDS in the SSPM. The concentration-time profile of the supersaturation and following precipitation was obtained in order to determine the induction time (tind) for detectable precipitation. The data showed that the absolute values of tind and aDS were not directly comparable between partners, however, upon linearization of the data a reproducible rank ordering of the three model compounds was obtained based on the ß-value, which was defined as the slope of the ln(tind) versus ln(aDS)-2 plot. Linear regression of this plot showed that aprepitant had the highest ß-value, 15.1, while felodipine and fenofibrate had comparable ß-values, 4.0 and 4.3, respectively. Of the five partners contributing with full data sets, 80% could obtain the same rank order for the three model compounds using the SSPM (aprepitant > felodipine ≈ fenofibrate). The α-value is dependent on the experimental setup and can be used as a parameter to evaluate the uniformity of the data set. This study indicated that the SSPM was able to obtain the same rank order of the ß-value between partners and, thus, that the SSPM may be used to classify compounds depending on their supersaturation propensity.

Identification and characterisation of a salt form of Danirixin with reduced pharmacokinetic variability in patient populations.

The natural variability of gastric pH or gastric acid reducing medications can result in lower and more variable clinical pharmacokinetics for basic compounds in patient populations. Progressing alternative salt forms with improved solubility and dissolution properties can minimise this concern. This manuscript outlines a nonclinical approach comprising multiple biopharmaceutical, in vitro and physiologically based pharmacokinetic model (PBPK) modelling studies to enable selection of an alternative salt form for danirixin (DNX, GSK1325756), a pharmaceutical agent being developed for chronic obstructive pulmonary disease (COPD). The hydrobromide salt of DNX was identified as having superior biopharmaceutical properties compared to the free base (FB) form in clinical development and the impact of switching to the hydrobromide salt (HBr) was predicted by integrating the nonclinical data in a PBPK model (using GastroPlus™) to enable simulation of clinical drug exposure with FB and HBr salts in the absence and presence of a gastric acid reducing comedication (omeprazole, a proton pump inhibitor (PPI)). Subsequent investigation of DNX pharmacokinetics in a Phase 1 clinical study comparing FB with HBr salt forms confirmed that DNX HBr had reduced the variability of drug exposure and that exposure was not affected by PPI co-administration with DNX HBr. This case study therefore adds to the surprisingly few examples of a more soluble salt of a weak base translating to an improvement in human pharmacokinetics and illustrates a clear clinical benefit of salt selection during drug development.

It's time for CMS to utilize functional assessment as a key quality component.

This editorial reviews the recently published study (AJMC April) by Gerrard et al, titled "Functional Status and Readmissions in Unilateral Hip Fractures," which analyzes the statistical prediction model of the Fitness Index Measure for hospital readmission in unilateral hip fractures, and discusses why functional assessment should be used in evaluating other conditions. The current method of stratifying risk for Core Measure Conditions used by CMS to predict hospital readmissions utilizes a largely nonmodifiable formula of age, gender, and medical comorbidities. Numerous recent studies have shown that validated functional assessment can be a powerful statistical predictor of hospital readmission. The author makes the argument for CMS to utilize functional assessment to predict hospital readmissions as a part of its Value-Based Purchasing Program.

Making a case for high-volume robotic surgery centers: A cost-effectiveness analysis of transoral robotic surgery.

OBJECTIVE: To evaluate the cost-effectiveness of transoral robotic surgery (TORS) compared to intensity-modulated radiotherapy (IMRT) for early stage (T1-2, N0, M0) oropharyngeal squamous cell carcinoma (OPSCC). PATIENTS AND METHODS: A Markov decision tree model with a 5-year time horizon was developed. Comparative groups were: i) TORS with concurrent ipsilateral neck dissection +/- adjunctive IMRT, and ii) primary IMRT. Primary outcome was cost/quality adjusted life year (QALY). Perspective was the United States third party payer. Costs and effects were discounted at a rate of 3.5%. A threshold and probabilistic sensitivity analysis were performed. RESULTS: TORS strategy cost $30,992 and provided 4.81 QALYs/patient. The IMRT strategy cost $26,033 and provided a total of 4.78 QALYs/patient. The incremental cost effectiveness ratio for TORS vs. IMRT in the reference case was $165,300/QALY. The probability that TORS is cost-effective compared to IMRT at a maximum willingness-to-pay threshold of $50,000/QALY is 42%. CONCLUSION: An IMRT strategy for management of early stage OPSCC is more likely to be cost-effective compared to TORS. To improve the value of TORS for early stage OPSCC, consolidating TORS procedures to create high-volume centers of excellence may be a potential strategy to increase incremental effectiveness and reduce incremental costs. J. Surg. Oncol. 2015 111:155-163. © 2015 Wiley Periodicals, Inc.

Application of QbD principles for the evaluation of empty hard capsules as an input parameter in formulation development and manufacturing.

Understanding the product and process variable on the final product performance is an essential part of the quality-by-design (QbD) principles in pharmaceutical development. The hard capsule is an established pharmaceutical dosage form used worldwide in development and manufacturing. The empty hard capsules are supplied as an excipient that is filled by pharmaceutical manufacturers with a variety of different formulations and products. To understand the potential variations of the empty hard capsules as an input parameter and its potential impact on the finished product quality, a study was performed investigating the critical quality parameters within and in between different batches of empty hard gelatin capsules. The variability of the hard capsules showed high consistency within the specification of the critical quality parameters. This also accounts for the disintegration times, when automatic endpoint detection was used. Based on these data, hard capsules can be considered as a suitable excipient for product development using QbD principles.

Care coordination measures of a family medicine residency as a model for hospital readmission reduction.

The processes of care coordination of patient transition from hospital to outpatient settings are an integral part of the Patient-Centered Medical Home. We report a cooperative initiative between our admission hospital and family medicine residency to analyze the discharge process using the Agency for Healthcare Research and Quality's Re-engineering Discharge initiative, focusing on efficient information transfer and communication with discharged patients to insure rapid follow-up in the clinic. Our project yielded markedly reduced readmission rates compared with both local hospital and national rates.

Specific and sensitive hydrolysis probe-based real-time PCR detection of epidermal growth factor receptor variant III in oral squamous cell carcinoma.

BACKGROUND: The tumor-specific EGFR deletion mutant, EGFRvIII, is characterised by ligand-independent constitutive signalling. Tumors expressing EGFRvIII are resistant to current EGFR-targeted therapy. The frequency of EGFRvIII in head and neck squamous cell carcinoma (HNSCC) is disputed and may vary by specific sub-site. The purpose of this study was to measure the occurrence of EGFRvIII mutations in a specific HNSCC subsite, oral squamous cell carcinoma (OSCC), using a novel real-time PCR assay. METHODOLOGY: Pre-treatment Formalin Fixed Paraffin Embedded (FFPE) cancer specimens from 50 OSCC patients were evaluated for the presence of EGFRvIII using a novel hydrolysis probe-based real-time PCR assay. EGFR protein expression in tumor samples was quantified using fluorescent immunohistochemistry (IHC) and AQUA® technology. PRINCIPAL FINDINGS: We detected EGFRvIII in a single OSCC patient in our cohort (2%). We confirmed the validity of our detection technique in an independent cohort of glioblastoma patients. We also compared the sensitivity and specificity of our novel real-time EGFRvIII detection assay to conventional RT-PCR and direct sequencing. Our assay can specifically detect EGFRvIII and can discriminate against wild-type EGFR in FFPE tumor samples. AQUAnalysis® revealed that the presence of EGFRvIII transcript is associated with very high EGFR protein expression (98(th) percentile). Contrary to previous reports, only 44% of OSCC over-expressed EGFR in our study. CONCLUSION AND SIGNIFICANCE: Our results suggest that the EGFRvIII mutation is rare in OSCC and corroborate previous reports of EGFRvIII expression only in tumors with extreme over-expression of EGFR. We conclude that EGFRvIII-specific therapies may not be ideally suited as first-line treatment in OSCC. Furthermore, highly specific and sensitive methods, such as the real-time RT-PCR assay and AQUAnalysis® described here, will provide accurate assessment of EGFR mutation frequency and EGFR expression, and will facilitate the selection of optimal tailored therapies for OSCC patients.

A triple-blinded randomized trial comparing the hemostatic effects of large-dose 10% hydroxyethyl starch 264/0.45 versus 5% albumin during major reconstructive surgery.

In Canada, hydroxyethyl starch 264/0.45 (HES 264/0.45; molar weight 264 kDa, molar substitution 0.45) has largely replaced albumin as the colloidal fluid of choice for perioperative intravascular volume expansion. The maximum recommended dose of HES 264/0.45 is 28 mL/kg; however, there are no clinical data supporting this limit. In this study we compared the hemostatic effects of HES 264/0.45 versus 5% albumin in doses up to 45 mL/kg over 24 h during major reconstructive head and neck surgery. Fifty patients were randomized to receive HES 264/0.45 or 5% human albumin from the induction of anesthesia until 24 h thereafter. Both albumin and HES 264/0.45 effectively maintained physiologic variables in the perioperative and postoperative periods. The partial thromboplastin time and international normalized ratio were significantly increased in the HES 264/0.45 group compared with the albumin group after infusion of 30 mL/kg and 45 mL/kg (P < 0.05). Factor VIII activity and von Willebrand factor level were significantly reduced in the HES 264/0.45 group compared with the albumin group after infusion of 15 mL/kg, 30 mL/kg, and 45 mL/kg (P < 0.05). Significantly more subjects in the HES 264/0.45 group received allogeneic red blood cell transfusions (P < 0.02). We conclude that HES 264/0.45 infusions >30 mL/kg over 24 h impair coagulation to a greater extent than albumin, possibly leading to more allogeneic transfusions.