Ten years survival results of randomized study comparing weekly vs. triweekly cisplatin with concurrent radiation in locally advanced carcinoma cervix.

Background: The current standard of treatment for locally advanced cervical cancer is concurrent chemo-radiation with improved overall survival (OS) by 6% with manageable toxicities. The cisplatin 40 mg/m2 given weekly is the widely practiced regimen for 4-6 cycles concurrently with irradiation. Materials and methods: Two hundred and twelve patients with histologically proven squamous cell carcinoma of cervix with stages IIB to IIIB were enrolled between 2007-2011. External beam radiation dose of 45 Gy in 25 fractions was delivered over 5 weeks. Brachytherapy was delivered by manual afterloading cesium-137 (Cs137) low dose brachytherapy (LDR) using modified Fletcher suit intracavitary applicators to a total dose of 30 Gy to Point A or interstitial template to dose of 21 Gy/3 fractions with remote afterloading iridium-192 (Ir192) high dose brachytherapy (HDR). Patients were randomized to arm A receiving 40 mg/m2 of concurrent cisplatin weekly and arm B receiving 100 mg/m2 of concurrent cisplatin triweekly. Results: One hundred and nine patients were randomized to weekly cisplatin and one hundred and three patients to triweekly cisplatin at the end of recruitment. At ten years, the OS was higher in the weekly arm (79.8%) compared to triweekly arm (70.9%). Disease free survival (DFS) was almost equal (76.1% and 73.8%) in the weekly and three-weekly arms. There is definite significance in overall DFS with patients receiving the cumulative cisplatin doses of more than 250 mg (p = 0.028). The patients with more than 45 years of age had better overall survival (OS) (79%) with statistical significance 31 (p = 0.020). Conclusion: Both cisplatin based triweekly and weekly concurrent chemotherapy are equally effective in terms of OS and DFS.

Treatment Efficacy Score-continuous residual cancer burden-based metric to compare neoadjuvant chemotherapy efficacy between randomized trial arms in breast cancer trials.

BACKGROUND: Difference in pathologic complete response (pCR) rate after neoadjuvant chemotherapy does not capture the impact of treatment on downstaging of residual cancer in the experimental arm. We developed a method to compare the entire distribution of residual cancer burden (RCB) values between clinical trial arms to better quantify the differences in cytotoxic efficacy of treatments. PATIENTS AND METHODS: The Treatment Efficacy Score (TES) reflects the area between the weighted cumulative distribution functions of RCB values from two trial arms. TES is based on a modified Kolmogorov-Smirnov test with added weight function to capture the importance of high RCB values and uses the area under the difference between two distribution functions as a statistical metric. The higher the TES the greater the shift to lower RCB values in the experimental arm. We developed TES from the durvalumab + olaparib arm (n = 72) and corresponding controls (n = 282) of the I-SPY2 trial. The 11 other experimental arms and control cohorts (n = 947) were used as validation sets to assess the performance of TES. We compared TES to Kolmogorov-Smirnov, Mann-Whitney, and Fisher's exact tests to identify trial arms with higher cytotoxic efficacy and assessed associations with trial arm level survival differences. Significance was assessed with a permutation test. RESULTS: In the validation set, TES identified arms with a higher pCR rate but was more accurate to identify regimens as less effective if treatment did not reduce the frequency of high RCB values, even if the pCR rate improved. The correlation between TES and survival was higher than the correlation between the pCR rate difference and survival. CONCLUSIONS: TES quantifies the difference between the entire distribution of pathologic responses observed in trial arms and could serve as a better early surrogate to predict trial arm level survival differences than pCR rate difference alone.

Relationship of low molecular weight fluorophore levels with clinical factors and fenofibrate effects in adults with type 2 diabetes.

People with diabetes are at risk of chronic complications and novel biomarkers, such as Advanced glycation end-products (AGEs) may help stratify this risk. We assessed whether plasma low-molecular weight AGEs, also known as LMW-fluorophores (LMW-F), are associated with risk factors, predict complications, and are altered by fenofibrate in adults with type 2 diabetes. Plasma LMW-F were quantified at baseline, after six weeks fenofibrate, and one year post-randomisation to fenofibrate or placebo. LMW-F associations with existing and new composite vascular complications were determined, and effects of fenofibrate assessed. LMW-F correlated positively with age, glycated haemoglobin (HbA1c), pulse pressure, kidney dysfunction and inflammation; and negatively with urate, body mass index, oxidative stress and leptin, albeit weakly (r = 0.04-0.16, all p < 0.01). Independent determinants of LMW-F included smoking, diastolic blood pressure, prior cardiovascular disease or microvascular complications, Caucasian ethnicity, kidney function, HbA1c and diabetes duration (all p ≤ 0.01). Baseline LMW-F tertiles correlated with on-trial macrovascular and microvascular complications (trend p < 0.001) on univariate analyses only. Six weeks of fenofibrate increased LMW-F levels by 21% (p < 0.001). In conclusion, LMW-F levels correlate with many risk factors and chronic diabetes complications, and are increased with fenofibrate. LMW-F tertiles predict complications, but not independently of traditional risk factors.

Predicted sensitivity to endocrine therapy for stage II-III hormone receptor-positive and HER2-negative (HR+/HER2-) breast cancer before chemo-endocrine therapy.

BACKGROUND: We proposed that a test for sensitivity to the adjuvant endocrine therapy component of treatment for patients with stage II-III breast cancer (SET2,3) should measure transcription related to estrogen and progesterone receptors (SETER/PR index) adjusted for a baseline prognostic index (BPI) combining clinical tumor and nodal stage with molecular subtype by RNA4 (ESR1, PGR, ERBB2, and AURKA). PATIENTS AND METHODS: Patients with clinically high-risk, hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative (HR+/HER2-) breast cancer received neoadjuvant taxane-anthracycline chemotherapy, surgery with measurement of residual cancer burden (RCB), and then adjuvant endocrine therapy. SET2,3 was measured from pre-treatment tumor biopsies, evaluated first in an MD Anderson Cancer Center (MDACC) cohort (n = 307, 11 years' follow-up, U133A microarrays), cut point was determined, and then independent, blinded evaluation was carried out in the I-SPY2 trial (n = 268, high-risk MammaPrint result, 3.8 years' follow-up, Agilent-44K microarrays, NCI Clinical Trials ID: NCT01042379). Primary outcome measure was distant relapse-free survival. Multivariate Cox regression models tested prognostic independence of SET2,3 relative to RCB and other molecular prognostic signatures, and whether other prognostic signatures could substitute for SETER/PR or RNA4 components of SET2,3. RESULTS: SET2,3 added independent prognostic information to RCB in the MDACC cohort: SET2,3 [hazard ratio (HR) 0.23, P = 0.004] and RCB (HR 1.77, P < 0.001); and the I-SPY2 trial: SET2,3 (HR 0.27, P = 0.031) and RCB (HR 1.68, P = 0.008). SET2,3 provided similar prognostic information irrespective of whether RCB-II or RCB-III after chemotherapy, and in both luminal subtypes. Conversely, RCB was most strongly prognostic in cancers with low SET2,3 status (MDACC P < 0.001, I-SPY2 P < 0.001). Other molecular signatures were not independently prognostic; they could effectively substitute for RNA4 subtype within the BPI component of SET2,3, but they could not effectively substitute for SETER/PR index. CONCLUSIONS: SET2,3 added independent prognostic information to chemotherapy response (RCB) and baseline prognostic score or subtype. Approximately 40% of patients with clinically high-risk HR+/HER2- disease had high SET2,3 and could be considered for clinical trials of neoadjuvant endocrine-based treatment.

Weekly vs. tri-weekly cisplatin based chemoradiation in carcinoma cervix: a prospective randomized study of toxicity and compliance.

BACKGROUND: Addition of chemotherapy to radiation has improved 5-year survival by 6%. However, the optimal dose and schedule of concurrent cisplatin is not well defined, though widely accepted practice is the weekly schedule of 40 mg/m2 for 5 weeks. Repeated admissions for weekly cisplatin drain the limited resources in high volume centres. We intended to study the compliance and toxicity of two cisplatin schedules in our patients diagnosed with carcinoma cervix. MATERIALS AND METHODS: Between 2007-2011, 212 patients, histologically proven squamous cell carcinoma with stages IIB to IIIB were randomized into two arms. All patients were planned for external beam radiotherapy 45 Gy/25 frs over 5 weeks followed by Intracavitary or Interstitial brachytherapy to a total BED dose of 75-85 Gy. Single agent cisplatin given concomitantly, was scheduled weekly (40 mg/m2/cycle, 5 cycles) in an arm A and three weekly (100 mg/m2/cycle, 2 cycles) in an arm B. Toxicity and compliance were evaluated weekly according to the RTOG guidelines. Analysis of the compiled data was done using SSPS version 20. RESULTS: Of the evaluable 212, 109 patients received weekly cisplatin chemotherapy and 103 patients received three weekly cisplatin. The most common acute toxicity observed was grade I-II leucopoenia. The upper and lower gastrointestinal reactions were high in three weekly arms, which was statistically significant (57% and 42.7%, p < 0.05). Proctitis was observed in 10% of patients in both of the arms and only two patients had Gr1 Cystitis after 6 months of treatment. CONCLUSIONS: Tri-weekly cisplatin based concurrent chemoradiation can be adopted in high volume centres with manageable haematological and gastrointestinal acute toxicities.

Effect of antibiotics on urine leakage in women with refractory detrusor overactivity: A phase IIb randomized trial.

AIM: Because bacterial cystitis is common in women with refractory detrusor overactivity, the aim was to compare the efficacy of 6 weeks of rotating antibiotics versus placebo, in conjunction with an anticholinergic, in controlling the symptoms of urge incontinence. METHODS: In a multicenter phase IIb double-blinded randomized placebo-controlled trial, women with urodynamically proven refractory detrusor overactivity were randomized in a 2:1 ratio of antibiotics versus placebo for 6 weeks, in addition to darifenacin for 6 months. Any woman with disabling cystitis symptoms was given appropriate antibiotics ("clinical override"). The primary outcome was the degree of urge incontinence change at 6 weeks and 6 months on 24-h pad test. Secondary outcomes were changes in leaks and voids per day measured on 3-day bladder diary and quality of life measures. Microbiological data were collected at all visits. RESULTS: Although 278 women were screened, only 36 were randomized and 33 (91.7%) completed the trial. Leakage on 24-h pad test decreased at 6 months by 75 g in patients receiving antibiotics versus 35 g in placebo. Cure of urge incontinence occurred at 6 months in 10/21 (48%) of antibiotics versus 2/12 (17%) of placebo. Clinical override, necessitating treatment of cystitis, occurred in 41.6% of placebo versus 16.7% of the antibiotic group by 6 months. CONCLUSION: Despite the small sample size, the study showed a significant reduction in pad leakage and leaks per day over 24 h in the active treatment group over a 6-month period. Nearly half of patients on placebo had disabling urinary tract infection symptoms that required clinical override treatment.

Design for preparation of more active cross-linked enzyme aggregates of Burkholderia cepacia lipase using palm fiber residue.

A new design of cross-linked enzyme aggregates (CLEAs) of Burkholderia cepacia lipase (BCL) based mainly on the use of lignocellulosic residue of palm fiber as an additive was proposed. Different parameters for the preparation of active CLEAs in the hydrolysis of olive oil, such as precipitation agents, crosslinking agent concentration, additives, and coating agents were investigated. The highest activity yield (121.1 ± 0.1%) and volumetric activity (1578.1 ± 2.5 U/mL) were achieved for CLEAs prepared using the combination of a coating step with Triton® X-100 and polyethyleneimine plus the use of palm fiber as an additive. The variations of the secondary structures of BCL-CLEAs were analyzed by second-derivative infrared spectra, mainly indicating a reduction of the α-helix structure, which was responsible for the lipase activation in the supramolecular structure of the CLEAs. Thus, these results provided evidence of an innovative design of BCL-CLEAs as a sustainable and biocompatible opportunity for biotechnology applications.

Linking structure to performance of Li1.2Mn0.54Ni0.13Co0.13O2 (Li and Mn rich NMC) cathode materials synthesized by different methods.

Li and Mn-rich Li1+xNiyCozMnwO2 (LMR-NMC, 0 < x < 0.2; w > 0.5) materials remain commercially relevant owing to their high specific capacity. Due to this stoichiometry, their synthesis forms always at least two phases: monoclinic Li2MnO3 and rhombohedral LiNiaCobMncO2 (a = b = c = 1) layered moieties. However, a complete understanding of their complex crystal structure has not yet been fully realized. The monoclinic phase may become electrochemically active only at high potentials (>4.6 V vs. Li). To complicate matters even more, it has been shown that the electrochemical performance of these materials, having formally the same stoichiometry, can vary with the chosen method of material synthesis. Identification of the chemical and/or structural reasons for these variations in performance is crucial to ensure the promotion of these important cathode materials towards a practical use. Yet most methods of analysis cannot distinguish the subtle, localized variations that account for such differences. Here, solid state 6,7Li NMR was found to be successful in identifying several distinctions between compounds with identical chemical formulae. Many distinctions can be made, and even suggested to account for some of the differences in the electrochemical behaviors noted for the differently prepared materials.

A prospective randomized study comparing concurrent chemoradiation with weekly and 3 weekly cisplatin in locally advanced oropharyngeal carcinoma.

INTRODUCTION: The chemotherapy schedules with cytotoxic dose or weekly regimes are still challenging, weighing the benefits versus toxicities. This prospective randomized study is an attempt to assess the efficacy of two schedules of cisplatin in management of locally advanced HNSCC. OBJECTIVES: The objectives of this study was to evaluate tolerance, tumour response and toxicities of concurrent chemoradiation with cisplatin in weekly and three weekly regimes. METHODS: Locally advanced oropharyngeal squamous cell carcinoma patients fit for concurrent chemoradiation with cisplatin 40 mg/m2 (weekly) and 100 mg/m2 (3 weekly) were randomized to Arm A and B concurrently with radiotherapy of 70Gy/35frs/7 weeks. STATISTICAL ANALYSIS: Chi-square/ Fisher Exact test has been used to find the significance of study parameters on categorical scale between the groups. The statistical software SPSS 15.0 was used. RESULTS: Between December 2010 and January 2013, 60 patients were enrolled. The median cycles of cisplatin in Arm-A was 5 and 2 in Arm-B. The complete response of 80.9% vs 75% and partial response of 14.3% vs 12.5% was observed in both arms respectively. There was no statistical difference in acute radiation and hematological toxicities between the two groups. With median follow up of 28 months, the 2 and 5 years overall survival was 55% and 58%; 41.6% and 32.3% in arms A and B respectively. CONCLUSION: In our study of locally advanced oropharyngeal carcinoma treated with radical radiotherapy comparing concurrent chemotherapy with cisplatin weekly vs 3 weekly had no significant difference in overall response, complete response and acute toxicities.

A combinatorial biomarker predicts pathologic complete response to neoadjuvant lapatinib and trastuzumab without chemotherapy in patients with HER2+ breast cancer.

BACKGROUND: HER2-positive (+) breast cancers, defined by HER2 overexpression and/or amplification, are often addicted to HER2 to maintain their malignant phenotype. Yet, some HER2+ tumors do not benefit from anti-HER2 therapy. We hypothesize that HER2 amplification levels and PI3K pathway activation are key determinants of response to HER2-targeted treatments without chemotherapy. PATIENTS AND METHODS: Baseline HER2+ tumors from patients treated with neoadjuvant lapatinib plus trastuzumab [with endocrine therapy for estrogen receptor (ER)+ tumors] in TBCRC006 (NCT00548184) were evaluated in a central laboratory for HER2 amplification by fluorescence in situ hybridization (FISH) (n = 56). HER2 copy number (CN) and FISH ratios, and PI3K pathway status, defined by PIK3CA mutations or PTEN levels by immunohistochemistry were available for 41 tumors. Results were correlated with pathologic complete response (pCR; no residual invasive tumor in breast). RESULTS: Thirteen of the 56 patients (23%) achieved pCR. None of the 11 patients with HER2 ratio <4 and/or CN <10 achieved pCR, whereas 13/45 patients (29%) with HER2 ratio ≥4 and/or CN ≥10 attained pCR (P = 0.0513). Of the 18 patients with tumors expressing high PTEN or wild-type (WT) PIK3CA (intact PI3K pathway), 7 (39%) achieved pCR, compared with 1/23 (4%) with PI3K pathway alterations (P = 0.0133). Seven of the 16 patients (44%) with HER2 ratio ≥4 and intact PI3K pathway achieved pCR, whereas only 1/25 (4%) patients not meeting these criteria achieved pCR (P = 0.0031). CONCLUSIONS: Our findings suggest that there is a clinical subtype in breast cancer with high HER2 amplification and intact PI3K pathway that is especially sensitive to HER2-targeted therapies without chemotherapy. A combination of HER2 FISH ratio and PI3K pathway status warrants validation to identify patients who may be treated with HER2-targeted therapy without chemotherapy.

Pembrolizumab monotherapy for previously untreated, PD-L1-positive, metastatic triple-negative breast cancer: cohort B of the phase II KEYNOTE-086 study.

BACKGROUND: Standard first-line treatment of metastatic triple-negative breast cancer (mTNBC) is chemotherapy. However, outcomes are poor, and new treatment options are needed. In cohort B of the phase II KEYNOTE-086 study, we evaluated pembrolizumab as first-line therapy for patients with PD-L1-positive mTNBC. PATIENTS AND METHODS: Eligible patients had centrally confirmed mTNBC, no prior systemic anticancer therapy for metastatic disease, measurable disease at baseline per RECIST v1.1 by central review, no radiographic evidence of central nervous system metastases, and a tumor PD-L1 combined positive score ≥1. Patients received pembrolizumab 200 mg intravenously every 3 weeks for up to 2 years. The primary end point was safety. Secondary end points included objective response rate, disease control rate (percentage of patients with complete or partial response or stable disease for ≥24 weeks), duration of response, progression-free survival and overall survival. RESULTS: All 84 patients enrolled were women, and 73 (86.9%) received prior (neo)adjuvant therapy. Fifty-three (63.1%) patients had treatment-related adverse events (AEs), including 8 patients (9.5%) with grade 3 severity; no patients experienced grade 4 AEs or died because of treatment-related AEs. Four patients had a complete response and 14 had a partial response, for an objective response rate of 21.4% (95% CI 13.9-31.4). Of the 13 patients with stable disease, 2 had stable disease lasting ≥24 weeks, for a disease control rate of 23.8% (95% CI 15.9-34.0). At data cut-off, 8 of 18 (44.4%) responses were ongoing, and median duration of response was 10.4 months (range 4.2 to 19.2+). Median progression-free survival was 2.1 months (95% CI 2.0-2.2), and median overall survival was 18.0 months (95% CI 12.9-23.0). CONCLUSIONS: Pembrolizumab monotherapy had a manageable safety profile and showed durable antitumor activity as first-line therapy for patients with PD-L1-positive mTNBC. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02447003.

Pembrolizumab monotherapy for previously treated metastatic triple-negative breast cancer: cohort A of the phase II KEYNOTE-086 study.

BACKGROUND: Treatment options for previously treated metastatic triple-negative breast cancer (mTNBC) are limited. In cohort A of the phase II KEYNOTE-086 study, we evaluated pembrolizumab as second or later line of treatment for patients with mTNBC. PATIENTS AND METHODS: Eligible patients had centrally confirmed mTNBC, ≥1 systemic therapy for metastatic disease, prior treatment with anthracycline and taxane in any disease setting, and progression on or after the most recent therapy. Patients received pembrolizumab 200 mg intravenously every 3 weeks for up to 2 years. Primary end points were objective response rate in the total and PD-L1-positive populations, and safety. Secondary end points included duration of response, disease control rate (percentage of patients with complete or partial response or stable disease for ≥24 weeks), progression-free survival, and overall survival. RESULTS: All enrolled patients (N = 170) were women, 61.8% had PD-L1-positive tumors, and 43.5% had received ≥3 previous lines of therapy for metastatic disease. ORR (95% CI) was 5.3% (2.7-9.9) in the total and 5.7% (2.4-12.2) in the PD-L1-positive populations. Disease control rate (95% CI) was 7.6% (4.4-12.7) and 9.5% (5.1-16.8), respectively. Median duration of response was not reached in the total (range, 1.2+-21.5+) and in the PD-L1-positive (range, 6.3-21.5+) populations. Median PFS was 2.0 months (95% CI, 1.9-2.0), and the 6-month rate was 14.9%. Median OS was 9.0 months (95% CI, 7.6-11.2), and the 6-month rate was 69.1%. Treatment-related adverse events occurred in 103 (60.6%) patients, including 22 (12.9%) with grade 3 or 4 AEs. There were no deaths due to AEs. CONCLUSIONS: Pembrolizumab monotherapy demonstrated durable antitumor activity in a subset of patients with previously treated mTNBC and had a manageable safety profile. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02447003.

Periodontitis is associated with disease severity and anti-double stranded DNA antibody and interferon-gamma levels in patients with systemic lupus erythematosus.

OBJECTIVES: To analyse the correlation between periodontitis severity and disease activity, anti-double stranded DNA (anti-dsDNA) antibody, and interferon-gamma (IFN-γ) levels in patients with systemic lupus erythematous (SLE). METHODS: We selected 61 patients with SLE (age 18-55 years) selected from a hospital in Malang, Indonesia. Clinical examination and laboratory tests were performed to assess disease activity. The severity of SLE was measured using the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), while periodontitis severity was measured according to the Periodontal Index (PI) criteria. Levels of anti-dsDNA and IFN-γ were determined using an enzyme-linked immunosorbent assay. Optical density at 450 nm was measured using an automated plate reader. RESULTS: The mean age of the subjects with SLE was 29 years, and mean disease duration was 2.8 years. Fifty-four of 61 (88.53%) subjects with SLE had periodontitis according to the PI. SLE subjects exhibited other clinical manifestations such as lupus nephritis, vasculitis, arthritis, mucocutaneous manifestation, fatigue, fever, and/or leukopenia. SLE severity was assessed according to the average SLEDAI score (17.70 ± 12.70), and average anti-dsDNA (122.6 ± 81.01 U/mL), and IFN-γ (14.64 ± 11.17 pg/mL) levels. There was a significantly positive correlation between periodontitis score and SLEDAI score (r = 0.927; p ≤ 0.0001), anti-dsDNA antibody (r = 0.948; p ≤ 0.0001), and IFN-γ (r = 0.951; p ≤ 0.0001) levels. CONCLUSION: Results of the present study demonstrated that periodontitis was associated with SLE disease activity, and was a biomarker of immune aging. Furthermore, this biomarker could be a reliable predictor of periodontal condition and prognosis of periodontitis and can also help in selecting the most appropriate treatment strategy for periodontitis in patients with SLE.

Rosai-Dorfman Disease - Five Years Retrospective Analysis from Tertiary Cancer Center.

AIM: To study the pattern of presentation and management of nodal and extranodal primary RDD. METHODOLOGY: From 2010 to 2015, eleven patients diagnosed with Rosai-Dorfman Disease (RDD) presented at our institute. Nine of them were analyzed as they received treatment at our center. We had five neck primaries, three intracranial and one cutaneous disease. Hematological, radiological, histopathological and immunohistochemistry evaluation along with the treatment data was collected and analyzed. RESULTS: Nine cases treated at our institute had a median follow up of 41 months. Four of the five neck node primaries were treated with corticosteroids. Of the four, two had complete and two partial responses locally. Remaining one patient had partial response to surgery and corticosteroids. Three patients with CNS presentation treated with radiotherapy to a total dose of 20-40 Gy, had complete response locally. However, two patients had simultaneous neck nodes during presentation. Partial response was seen with corticosteroids alone in one and with radiation to the neck in the other patient, of which one succumbed to myocardial infarction within 3 months post treatment. Two of them received re-irradiation to the recurrent lesions with good results. CONCLUSION: Due to its rarity there is no particular guidelines regarding the management of patients with RDD. We conclude that low dose radiation either in combination with surgery or corticosteroids in nodal or extranodal lesions has shown a better local control.

A review of NMR methods used in the study of the structure and dynamics of ionic liquids.

Recently, NMR spectroscopy has been emerging out as a powerful tool to study the structure and dynamics of ionic liquids (ILs) and ILs-Li+ salt mixtures. This mini-review primarily focuses on the applications of various NMR spectroscopic techniques such as self-diffusion measurements, NMR relaxometry, two-dimensional NMR, and other novel NMR approaches to study the structure and dynamics of ILs and its mixtures with lithium salts. Copyright © 2017 John Wiley & Sons, Ltd.

PTH [1-34]-induced alterations predispose the mandibular condylar cartilage to mineralization.

OBJECTIVE: To study the effects of intermittent parathyroid hormone (PTH [1-34]) on the mandibular condylar cartilage (MCC) and subchondral bone in adult female mice. MATERIALS AND METHODS: Twenty-two, 20-week-old female mice were used for in vivo experiments. The experimental mice (n=11) received daily intraperitoneal injections of PTH [1-34] for 3 weeks, while control mice (n=11) received intraperitoneal injections of 0.9% saline solution. Mice were euthanized and then micro-computed tomography (micro-CT); histology and immunostaining were carried out to assess the response. RESULTS: Intermittent PTH [1-34] led to early MCC breakdown and surface irregularities. Micro-CT analyses indicated that PTH [1-34] treatment led to increased bone volume fraction, tissue density and trabecular thickness, while decreasing the trabecular spacing. Histological analyses showed decreased proteoglycan secretion, increased bone turnover (TRAP staining) and increased mineralization. Furthermore, PTH [1-34] treatment showed increased apoptosis of the cells. Our immunohistochemistry showed increased expression of pSMAD158 in the MCC and subchondral bone with PTH administration, whereas sclerostin (SOST) expression was decreased. CONCLUSIONS: Intermittent PTH [1-34] results in early mineralization of the MCC, which may result in cartilage degeneration. Our results identified a novel mechanism by which PTH [1-34] induces alteration in the microarchitecture of the MCC and the subchondral bone.

Pharmacogenomics-Based Point-of-Care Clinical Decision Support Significantly Alters Drug Prescribing.

Changes in behavior are necessary to apply genomic discoveries to practice. We prospectively studied medication changes made by providers representing eight different medicine specialty clinics whose patients had submitted to preemptive pharmacogenomic genotyping. An institutional clinical decision support (CDS) system provided pharmacogenomic results using traffic light alerts: green = genomically favorable, yellow = genomic caution, red = high risk. The influence of pharmacogenomic alerts on prescribing behaviors was the primary endpoint. In all, 2,279 outpatient encounters were analyzed. Independent of other potential prescribing mediators, medications with high pharmacogenomic risk were changed significantly more often than prescription drugs lacking pharmacogenomic information (odds ratio (OR) = 26.2 (9.0-75.3), P < 0.0001). Medications with cautionary pharmacogenomic information were also changed more frequently (OR = 2.4 (1.7-3.5), P < 0.0001). No pharmacogenomically high-risk medications were prescribed during the entire study when physicians consulted the CDS tool. Pharmacogenomic information improved prescribing in patterns aimed at reducing patient risk, demonstrating that enhanced prescription decision-making is achievable through clinical integration of genomic medicine.

Patient Perceptions of Care as Influenced by a Large Institutional Pharmacogenomic Implementation Program.

Despite growing clinical use of genomic information, patient perceptions of genomic-based care are poorly understood. We prospectively studied patient-physician pairs who participated in an institutional pharmacogenomic implementation program. Trust/privacy/empathy/medical decision-making (MDM)/personalized care dimensions were assessed through patient surveys after clinic visits at which physicians had access to preemptive pharmacogenomic results (Likert scale, 1 = minimum/5 = maximum; mean [SD]). From 2012-2015, 1,261 surveys were issued to 507 patients, with 792 (62.8%) returned. Privacy, empathy, MDM, and personalized care scores were significantly higher after visits when physicians considered pharmacogenomic results. Importantly, personalized care scores were significantly higher after physicians used pharmacogenomic information to guide medication changes (4.0 [1.4] vs. 3.0 [1.6]; P < 0.001) compared with prescribing visits without genomic guidance. Multivariable modeling controlling for clinical factors confirmed personalized care scores were more favorable after visits with genomic-influenced prescribing (odds ratio [OR] = 3.26; 95% confidence interval [CI] = (1.31-8.14); P < 0.05). Physicians seem to individualize care when utilizing pharmacogenomic results and this decision-making augmentation is perceived positively by patients.

Unusual linear dependency of viscosity with temperature in ionic liquid/water mixtures.

An unusual linear dependency of viscosity with temperature has been observed in aqueous solutions of 1-octyl-3-methylimidazolium-based ionic liquids because of the ion induced structural transition which leads to the violation of both the Stokes-Einstein and fractional Stokes-Einstein equations, suggesting the presence of dynamic heterogeneity in the system.