Research Spotlight

Raikin, S. M., K. Sandrowski, J. M. Kane, D. Beck and B. S. Winters (2017). “Midterm outcome of the agility total ankle arthroplasty.” Foot Ankle Int 38(6): 662-670.

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BACKGROUND: Ankle arthritis is a debilitating condition that causes severe functional impairment. While arthrodesis has been the gold standard of surgical treatment for this condition, significant improvements in total ankle arthroplasty have made it a viable alternative. The purpose of this study was to look at the midterm follow-up of the Agility total ankle. METHODS: A retrospective review of prospectively collected data was conducted on 127 consecutive Agility total ankles implanted between 2002 and 2009. Charts were reviewed to collect patient demographics. In addition, coronal alignment, overall arc of motion, tibiotalar component motion, syndesmotic fusion, zones of osteolysis, and subsidence were determined. A Kaplan-Meier survival and linear regression analysis were used to predict implant failure. A multivariate regression analysis was used to assess whether radiographic measures were predictive of patient satisfaction. RESULTS: Ninety (78.2%) of 115 patients retained their primary implant, of which 105 were available for evaluation, with an average follow-up of 9.1 years. Twenty-five had their implant removed. The average score for the Foot and Ankle Ability Measure (FAAM) activities of daily living subscale was 82.4, FAAM sport subscale 55.3, postoperative visual analog scale (VAS) for pain 12.7, and Short Form-12 (SF-12) Health Survey physical component 45.8 and SF-12 mental component 56.1. Average arc of motion across the implant was 22.3 and 6.3 degrees in adjacent joints. Osteolysis most commonly occurred in zones 1 and 6. No statistical differences were found in the rate or location of subsidence. Linear regression analysis demonstrated that age at the time of surgery was predictive of failure ( P = .036). Inflammatory and atraumatic arthritis demonstrated higher likelihoods of revision. No correlation was detected between radiographic parameters and outcomes scores ( P > .05; rho >0.2). A significant reduction in mean VAS pain scores by 67.6% was maintained at an average of 8 years. DISCUSSION: Our results were improved over the nondesigner outcomes published in the current literature. Survivorship approached 80% at 9 years, with Kaplan-Meier 14-year survival calculated at 70.4%. Patients with their original implant were functioning with a high level of satisfaction based on statistically validated outcome scores, which was independent of the radiographic appearance of their implant. Age at the time of surgery and inflammatory/atraumatic arthritis were predictive of failure.

Arostegui, J. I., J. Anton, I. Calvo, A. Robles, E. Iglesias, B. Lopez-Montesinos, R. Banchereau, S. Hong, Y. Joubert, G. Junge, V. Pascual and J. Yague (2017). “Open-label, phase ii study to assess efficacy and safety of canakinumab treatment in active hyperimmunoglobulinemia d with periodic fever syndrome.” Arthritis Rheumatol: 2017 May [Epub ahead of print].

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OBJECTIVE: To evaluate the efficacy and safety of canakinumab treatment in active hyperimmunoglobulinemia D with periodic fever syndrome (HIDS). METHODS: This was a 3-part, open-label study with a 6-month treatment period (P1; 300 mg or 4 mg/kg q6w), a 6-month withdrawal period (P2), and a 24-month treatment period (P3). The primary endpoint was reduction in frequency of attacks during treatment period compared with the historical period (HP; period in which patients did not receive drugs other than NSAIDs and/or steroids). RESULTS: All nine patients completed P1 and P2, whereas only eight completed P3. All patients achieved a complete response during P1, and only two required dose adjustments. The median number of attacks per patient decreased from 5 (3-12) during HP to 0 (0-2) during P1. During P2, seven out of nine patients flared with a median of 110 days (62-196) after the last canakinumab dose. Laboratory parameters were normalized at Day 15 and remained at normal levels throughout the study. The blood transcriptome assessed during P1 showed upregulated interferon and myeloid-related inflammatory responses in untreated patients compared to healthy controls, which rapidly decreased following canakinumab injection, reaching levels comparable to those of healthy controls. At least one adverse event (AE) was detected in all nine patients; most of them being mild in intensity, with infections being the most frequent AE. Serious AEs were reported in four patients. CONCLUSIONS: This study demonstrated the efficacy and safety of canakinumab treatment to control active HIDS and to suppress inflammatory transcriptional responses.

Becerra, C. R., K. Yoshida, H. Mizuguchi, M. Patel and D. Von Hoff (2017). “A phase 1, open-label, randomized, crossover study evaluating the bioavailability of tas-102 (trifluridine/tipiracil) tablets relative to an oral solution containing equivalent amounts of trifluridine and tipiracil.” J Clin Pharmacol 57(6): 751-759.

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TAS-102 (trifluridine/tipiracil) is composed of an antineoplastic thymidine-based nucleoside analogue trifluridine (FTD), and a thymidine phosphorylase inhibitor, tipiracil (TPI), at a molar ratio of 1:0.5 (weight ratio, 1:0.471). A phase 1 study evaluated relative bioavailability of TAS-102 tablets compared with an oral solution containing equivalent amounts of FTD and TPI. In an open-label, 2-sequence, 3-period, crossover bioavailability study (part 1), patients 18 years or older with advanced solid tumors were randomized to receive TAS-102 tablets (60 mg; 3 x 20-mg tablets) on day 1 and TAS-102 oral solution (60 mg) on days 8 and 15, or the opposite sequence. In an extension (part 2), all patients received TAS-102 tablets. Of the 46 patients treated in the crossover study, 38 were evaluable in the crossover bioavailability pharmacokinetic population. For area under the concentration-time curve (AUC)0-infinity and AUC0-last for FTD and TPI, and maximum plasma concentration (Cmax ) for TPI, the 90% confidence intervals (CIs) of the geometric mean ratios were within the 0.80 to 1.25 boundary for demonstration of bioequivalence; for FTD Cmax , the lower limit of the 90%CI was 0.786. The most frequently reported treatment-related grade 3 or 4 adverse events were neutropenia (7 patients) and decreased neutrophil count (3 patients). Although the lower limit of the 90%CI for the geometric mean ratio of FTD Cmax was slightly lower than 0.80, the bioavailability of the TAS-102 tablet is considered clinically similar to that of a TAS-102 oral solution. TAS-102 was well tolerated in this population of patients with advanced solid tumors.

Busse, L. W., X. S. Wang, D. M. Chalikonda, K. W. Finkel, A. K. Khanna, H. M. Szerlip, D. Yoo, S. L. Dana and L. S. Chawla (2017). “Clinical experience with iv angiotensin ii administration: A systematic review of safety.” Crit Care Med: 2017 May [Epub ahead of print].

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OBJECTIVE: Angiotensin II is an endogenous hormone with vasopressor and endocrine activities. This is a systematic review of the safety of IV angiotensin II. DATA SOURCES: PubMed, Medline, Scopus, and Cochrane. STUDY SELECTION: Studies in which human subjects received IV angiotensin II were selected whether or not safety was discussed. DATA EXTRACTION: In total, 18,468 studies were screened by two reviewers and one arbiter. One thousand one hundred twenty-four studies, in which 31,281 participants received angiotensin II (0.5-3,780 ng/kg/min), were selected. Data recorded included number of subjects, comorbidities, angiotensin II dose and duration, pressor effects, other physiologic and side effects, and adverse events. DATA SYNTHESIS: The most common nonpressor effects included changes in plasma aldosterone, renal function, cardiac variables, and electrolytes. Adverse events were infrequent and included headache, chest pressure, and orthostatic symptoms. The most serious side effects were exacerbation of left ventricular failure in patients with congestive heart failure and bronchoconstriction. One patient with congestive heart failure died from refractory left ventricular failure. Refractory hypotensive shock was fatal in 55 of 115 patients treated with angiotensin II in case studies, cohort studies, and one placebo-controlled study. One healthy subject died after a pressor dose of angiotensin II was infused continuously for 6 days. No other serious adverse events attributable to angiotensin II were reported. Heterogeneity in study design prevented meta-analysis. CONCLUSION: Adverse events associated with angiotensin II were infrequent; however, exacerbation of asthma and congestive heart failure and one fatal cerebral hemorrhage were reported.

Cheng, Y. L., L. Jordan, H. S. Chen, D. Kang, L. Oxford, J. Plemons, H. Parks and T. Rees (2017). “Chronic periodontitis can affect the levels of potential oral cancer salivary mrna biomarkers.” J Periodontal Res 52(3): 428-437.

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BACKGROUND AND OBJECTIVE: More than 100 salivary constituents have been found to show levels significantly different in patients with oral squamous cell carcinoma (OSCC) from those found in healthy controls, and therefore have been suggested to be potential salivary biomarkers for OSCC detection. However, many of these potential OSCC salivary biomarkers are also involved in chronic inflammation, and whether the levels of these biomarkers could be affected by the presence of chronic periodontitis was not known. The objective of this pilot study was therefore to measure the levels of seven previously reported potential OSCC salivary mRNA biomarkers in patients with chronic periodontitis and compare them to levels found in patients with OSCC and healthy controls. The seven salivary mRNAs were interleukin (IL)-8, IL-1beta, dual specificity phosphatase 1, H3 histone family 3A, ornithine decarboxylase antizyme 1, S100 calcium-binding protein P (S100P) and spermidine/spermine N1-acetyltransferase 1. MATERIAL AND METHODS: Unstimulated whole saliva samples were collected from a total of 105 human subjects from the following four study groups: OSCC; CPNS (chronic periodontitis, moderate to severe degree, non-smokers); CPS (chronic periodontitis, moderate to severe degree, smokers); and healthy controls. Levels of each mRNA in patient groups (OSCC or chronic periodontitis) relative to the healthy controls were determined by a pre-amplification reverse transcription-quantitative polymerase chain reaction approach with nested gene-specific primers. Results were recorded and analyzed by the Bio-Rad CFX96 Real-Time System. Mean fold changes between each pair of patient vs. control groups were analyzed by the Mann-Whitney U-test with Bonferroni corrections. RESULTS: Only S100P showed significantly higher levels in patients with OSCC compared to both patients with CPNS (p = 0.003) and CPS (p = 0.007). The difference in S100P levels between patients with OSCC and healthy controls was also marginally significant (p = 0.009). There was no significant difference in the levels of salivary IL-8, IL-1beta and dual specificity phosphatase 1 mRNAs between patients with OSCC and patients with CPNS (p = 0.510, 0.058 and 0.078, respectively); no significant difference in levels of salivary ornithine decarboxylase antizyme 1 and spermine N1-acetyltransferase mRNAs between patients with OSCC and patients with CPS (p = 0.318 and 0.764, respectively); and no significant difference in levels of the H3 histone family 3A mRNA between patients with OSCC and either CPS (p = 0.449) or healthy controls (p = 0.107). CONCLUSIONS: Salivary S100P mRNA could be a reliable biomarker for OSCC detection, regardless of the presence of chronic periodontitis. The presence of chronic periodontitis could significantly affect the levels of the other six mRNAs, and negatively influence reliability for using them as biomarkers for oral cancer detection.