Real-world evidence analysis of palbociclib prescribing patterns for patients with advanced/metastatic breast cancer treated in community oncology practice in the USA one year post approval.

BACKGROUND: Rapidly evolving understanding of cancer biology has presented novel opportunities to translate that understanding into clinically relevant therapy. Palbociclib, a novel, first-in-class cyclin-dependent kinase (CDK) 4/6 inhibitor was approved in the USA in February 2015 for the treatment of advanced/metastatic breast cancer. We examined real-world evidence in the first year post approval to understand the clinical and demographic characteristics of patients treated with palbociclib in community oncology practices and the dosing, treatment, and complete blood count (CBC) monitoring patterns. METHODS: This was a retrospective observational study of structured data from a US electronic medical record (EMR) database. Female patients receiving palbociclib after 31 January 2015 were followed through 31 March 2016. Our methodological rules were constructed to aggregate drugs received according to the order in which they are given, i.e., identify the line of therapy as first, second, or third line, etc., using treatment order and course description fields from the EMR. RESULTS: There were 763 patients initiating palbociclib who met the selection criteria. Of those, 612 (80.2%) received palbociclib concomitantly with letrozole. Mean follow up was 6.4 months and mean age at palbociclib initiation was 64 years. Of patients with a known starting dose (n = 417), 79.9% started on palbociclib 125 mg. Dose reductions were observed in 20.1% of patients. Percentages of patients according to line of therapy at initiation of palbociclib were first-line, 39.5%; second-line, 15.7%; third-line, 13.1%; and fourth-line therapy or later, 31.7%. On average, two CBC tests were conducted during the first cycle of palbociclib treatment. Overall, 74.6% of patients had a neutropenic event during follow up including 47.3% and 8.0% of patients with a grade 3 or 4 occurrence, respectively. CONCLUSIONS: Real-world palbociclib use one year post US approval demonstrates a more heterogeneous patient population than that studied in the clinical trials with more than half of the patients receiving palbociclib plus letrozole in later lines of therapy. CBC testing rates suggested good provider compliance with monitoring guidelines in the USA prescribing information. The occurrence of grade 3 and 4 neutropenia (based on laboratory results) was consistent with the rates of grade 3 and 4 neutropenia in two phase-III studies (PALOMA-2, 56% and 10%; PALOMA-3, 55% and 11%, respectively). Understanding palbociclib utilization in real-world patients and how drug dosing and monitoring are performed aids in the understanding of safe and effective use of the drug.

Adherence and persistence of mirabegron and anticholinergic therapies in patients with overactive bladder: a real-world claims data analysis.

BACKGROUND: Adherence and persistence rates of anticholinergic (ACH) therapies have been well described. To date, few studies describe these metrics for mirabegron in patients with overactive bladder. METHODS: This retrospective analysis of MarketScan® database assessed adherence and persistence of patients receiving either mirabegron or ACH. Study eligibility required an index date (first prescription filled) between July 2012 and June 2013 with 12 months of continuous enrolment preindex date and 12 months of follow-up. Adherence was defined as a proportion of days covered of ≥ 80% among patients with at least 2 fills of index medication. Persistence measures included treatment failure described as either treatment discontinuation (medication supply gap ≥ 30 days) or switching to a different medication. A medication supply gap of ≥ 45 days was used as a sensitivity analysis. RESULTS: The mean age of mirabegron users (n = 4037) was 67 years and 43% were ACH naïve while the mean age of ACH users was 62 years (n = 67,943). Over the 12-month follow-up period, 44% of patients treated with mirabegron and 31% of patients treated with ACH were adherent to their indexed medications. Treatment failure was 81% for mirabegron and 88% for ACH. Most mirabegron treatment failures were because of treatment discontinuation (67%) versus switching to ACH therapy (14%). The ACH discontinuation rate was 84% and treatment switching rate was 4%. The mean (standard deviation) time to treatment failure was 143 (130) days for mirabegron and 69 (69) days for ACH. Adherence and persistence patterns were similar in the sensitivity analysis using a ≥ 45-day supply gap threshold. CONCLUSIONS: This real-world study demonstrated low adherence and persistence to mirabegron similar to ACH therapies.

Temperature-Dependent Henry's Law Constants of Atmospheric Amines.

There has been growing interest in understanding atmospheric amines in the gas phase and their mass transfer to the aqueous phase because of their potential roles in cloud chemistry, secondary organic aerosol formation, and the fate of atmospheric organics. Temperature-dependent Henry's law constants (KH) of atmospheric amines, a key parameter in atmospheric chemical transport models to account for mass transfer, are mostly unavailable. In this work, we investigated gas-liquid equilibria of five prevalent atmospheric amines, namely 1-propylamine, di-n-propylamine, trimethylamine, allylamine, and 4-methylmorpholine using bubble column technique. We reported effective KH, intrinsic KH, and gas phase diffusion coefficients of these species over a range of temperatures relevant to the lower atmosphere for the first time. The measured KH at 298 K and enthalpy of solution for 1-propylamine, di-n-propylamine, trimethylamine, allylamine, and 4-methylmorpholine are 61.4 ± 4.9 mol L(-1) atm(-1) and -49.0 ± 4.8 kJ mol(-1); 14.5 ± 1.2 mol L(-1) atm(-1) and -72.5 ± 6.8 kJ mol(-1); 8.9 ± 0.7 mol L(-1) atm(-1) and -49.6 ± 4.7 kJ mol(-1); 103.5 ± 10.4 mol L(-1) atm(-1) and -42.7 ± 4.3 kJ mol(-1); and 952.2 ± 114.3 mol L(-1) atm(-1) and -82.7 ± 9.7 kJ mol(-1), respectively. In addition, we evaluated amines' characteristic times to achieve gas-liquid equilibrium for partitioning between gas and aqueous phases. Results show gas-liquid equilibrium can be rapidly established at natural cloud droplets surface, but the characteristic times may be extended substantially at lower temperatures and pHs. Moreover, our findings imply that atmospheric amines are more likely to exist in cloud droplets, and ambient temperature, water content, and pH of aerosols play important roles in their partitioning.

Temperature-dependent deliquescent and efflorescent properties of methanesulfonate sodium studied by ATR-FTIR spectroscopy.

Modeling of aerosols and cloud formation processes in the marine boundary layer (MBL) require extensive data on hygroscopic properties of relevant methanesulfonate particles, which are currently scarce. In this work, methanesulfonate sodium (CH3SO3Na, MSA-Na), the most abundant methanesulfonate salt, was selected, and its deliquescent and efflorescent properties at temperatures relevant to the lower troposphere were studied using an ATR-FTIR flow system. To validate the approach, we investigated hygroscopic properties of NaCl particles, and our measured deliquescent relative humidity (DRH) and efflorescent relative humidity (ERH) of the NaCl particles obtained from the changes in integrated absorbance of water peaks in infrared spectra agreed with literature data well. We then reported DRH and ERH of MSA-Na particles as a function of temperature for the first time using both the changes in integrated absorbance of water peaks and the changes in peak position and shape of CH3SO3(-) symmetric and asymmetric vibrational modes. Our experiments showed that MSA-Na particles present quite different temperature-dependent hygroscopic behaviors from NaCl. Both the DRH and ERH of MSA-Na particles increase with decreasing temperatures. Due to the significant differences in temperature-dependent DRH and ERH, NaCl particles, if processed in MBL by methanesulfonic acid, are expected to deliquesce slightly earlier during a hydration process but effloresce at a much earlier stage during a dehydration process, especially at lower temperatures. This could considerably influence phase, size, and water content of sea salt aerosols and consequently their reactivity, lifetime, and impacts on atmospheric chemistry and climate systems.

Temperature-dependent Henry's law constants of atmospheric organics of biogenic origin.

There have been growing interests in modeling studies to understand oxidation of volatile organic compounds in the gas phase and their mass transfer to the aqueous phase for their potential roles in cloud chemistry, formation of secondary organic aerosols, and fate of atmospheric organics. Temperature-dependent Henry's law constants, key parameters in the atmospheric models to account for mass transfer, are often unavailable. In the present work, we investigated gas-liquid equilibriums of isoprene, limonene, α-pinene, and linalool using a bubble column technique. These compounds, originating from biogenic sources, were selected for their implications in atmospheric cloud chemistry and secondary organic aerosol formation. We reported Henry's law constants (K(H)), first order loss rates (k), and gas phase diffusion coefficients over a range of temperatures relevant to the lower atmosphere (278-298 K) for the first time. The measurement results of K(H) values for isoprene, limonene, α-pinene, and linalool at 298 K were 0.036 ± 0.003; 0.048 ± 0.004; 0.029 ± 0.004; and 21.20 ± 0.30 mol L(-1) atm(-1), respectively. The fraction for these compounds in stratocumulus and cumulonimbus clouds at 278 K were also estimated in this work (isoprene, 1.0 × 10(-6), 6.8 × 10(-6); limonene, 1.5 × 10(-6), 1.0 × 10(-5); α-pinene, 4.5 × 10(-7), 3.1 × 10(-6); and linalool, 6.2 × 10(-4), 4.2 × 10(-3)). Our measurements in combination with literature results indicated that noncyclic alkenes could have smaller K(H) values than those of cyclic terpenes and that K(H) values may increase with an increasing number of double bonds. It was also shown that estimated Henry's law constants and their temperature dependence based on model prediction can differ from experimental results considerably and that direct measurements of temperature-dependent Henry's law constants of atmospheric organics are necessary for future work.

Indicator microbes correlate with pathogenic bacteria, yeasts and helminthes in sand at a subtropical recreational beach site.

AIMS: Research into the relationship between pathogens, faecal indicator microbes and environmental factors in beach sand has been limited, yet vital to the understanding of the microbial relationship between sand and the water column and to the improvement of criteria for better human health protection at beaches. The objectives of this study were to evaluate the presence and distribution of pathogens in various zones of beach sand (subtidal, intertidal and supratidal) and to assess their relationship with environmental parameters and indicator microbes at a non-point source subtropical marine beach. METHODS AND RESULTS: In this exploratory study in subtropical Miami (Florida, USA), beach sand samples were collected and analysed over the course of 6 days for several pathogens, microbial source tracking markers and indicator microbes. An inverse correlation between moisture content and most indicator microbes was found. Significant associations were identified between some indicator microbes and pathogens (such as nematode larvae and yeasts in the genus Candida), which are from classes of microbes that are rarely evaluated in the context of recreational beach use. CONCLUSIONS: Results indicate that indicator microbes may predict the presence of some of the pathogens, in particular helminthes, yeasts and the bacterial pathogen Staphylococcus aureus including methicillin-resistant forms. Indicator microbes may thus be useful for monitoring beach sand and water quality at non-point source beaches. SIGNIFICANCE AND IMPACT OF THE STUDY: The presence of both indicator microbes and pathogens in beach sand provides one possible explanation for human health effects reported at non-point sources beaches.

Neoadjuvant androgen ablation in localized carcinoma of the prostate.

BACKGROUND: An increased awareness of prostate cancer has led to a rise in the detection of this disease at a clinically localized stage at presentation. This article discusses the role of neoadjuvant hormonal ablation at this earlier stage to decrease tumor bulk and thus enhance survival. METHODS: Outcomes from each primary modality for localized treatment of prostate cancer with and without neoadjuvant androgen deprivation (NAAD) are reviewed. RESULTS: Survival benefit using NAAD has not yet been demonstrated from prostatectomy. Long-term hormonal deprivation provides an improved time to progression and has decreased distant metastatic and biochemical failure for poor-risk patients undergoing external-beam radiation. The toxicities of brachytherapy can be decreased with NAAD. CONCLUSIONS: NAAD with radical prostatectomy is considered to be investigational. The duration of NAAD needs to be delineated for poor-prognosis patients who are treated with external-beam radiation therapy, but the approach improves the local toxicity of brachytherapy.

The treatment challenge of hormone-refractory prostate cancer.

BACKGROUND: Both the demographics and treatment of hormone-refractory prostate cancer (HRPC) are changing. Patients are younger and healthier, with fewer comorbidities. The "no treatment until symptoms" approach is disappearing. Chemotherapy is increasingly being utilized. METHODS: The authors review the steps involved in hormone management before chemotherapy is considered. The roles for chemotherapy in current clinical trials are examined. RESULTS: Effective hormonal management of the prostate cancer patient incorporates an understanding of the stages of hormone sensitivity and prescribing additional interventions beyond simple castration. Once hormone refractoriness is established, the combination of mitoxantrone and prednisone has become a standard chemotherapeutic approach. New agents such as docetaxel are being tested in phase III trials against mitoxantrone plus prednisone. CONCLUSIONS: HRPC is now regarded as a chemotherapy-sensitive tumor. The goals of chemotherapy in HRPC are to decrease PSA level and improve quality of life. New agents and combinations are needed to improve survival.

Development of CPR security using impact analysis.

The HIPAA regulations will require that institutions ensure the prevention of unauthorized access to electronically stored or transmitted patient records. This paper discusses a process for analyzing the impact of security mechanisms on users of computerized patient records through "behind the scenes" electronic access audits. In this way, those impacts can be assessed and refined to an acceptable standard prior to implementation. Through an iterative process of design and evaluation, we develop security algorithms that will protect electronic health information from improper access, alteration or loss, while minimally affecting the flow of work of the user population as a whole.

Feasibility trial of postoperative radiotherapy and cisplatin followed by three courses of 5-FU and cisplatin in patients with resected head and neck cancer: a Southwest Oncology Group study.

BACKGROUND: Appropriate adjuvant chemotherapy for resected head and neck cancer patients has yet to be defined. Multiple trials have noted trends toward improved disease-free survival and local control. The Southwest Oncology Group undertook a feasibility trial of postoperative cisplatin and radiotherapy followed by three cycles of cisplatin and 5-fluorouracil. METHODS: Patients with resected stage III or IV head and neck cancer received cisplatin, 100 mg/m2, on days 1, 22, and 43 of radiotherapy. This therapy was followed by three cycles of cisplatin, 100 mg/m2 or last tolerated dose, and 5-fluorouracil, 1000 mg/m2, on days 1 to 4 every 21 days. RESULTS: Seventy-two patients from 22 institutions were registered; 68 were evaluable. Sixty-eight patients received radiotherapy. Only 25 of 68 patients (36.7%) were able to complete all six cycles of chemotherapy. Forty-three of 68 patients (63%) completed all three cycles with radiotherapy. Toxicities were tolerable. One toxic death occurred. CONCLUSIONS: It is not feasible to deliver six cycles of chemotherapy postoperatively in the sequence described. Compliance issues need further exploration to define effective adjuvant chemotherapy for head and neck patients.

Continuous-infusion 5-fluorouracil and cisplatin for advanced/recurrent transitional cell cancer of the bladder: a Southwest Oncology Group trial.

Significant toxicities result from the use of MVAC (methotrexate, vinblastine, adriamycin, cisplatin) for advanced/ recurrent transitional cell carcinoma of the bladder (ARTCCB). An alternative regimen of 5-fluorouracil (5-FU) and cisplatin was evaluated by Southwest Oncology Group (SWOG). Thirty-eight patients with ARTCCB were treated with continuous infusion 5-FU 1,000 mg/m2/days 1-5 and cisplatin 100 mg/day 1, on a every-21-days schedule. There were two complete responses (CR) and eight partial responses (PR) among 36 eligible patients, for an overall response rate of 28% [95% confidence interval (CI) 14-45%]. Median duration of response was 6 months, and median duration of survival was 9 months. No toxic deaths occurred. Grade 4 leukopenia occurred in 5 patients. Other toxicities were mild. Only two documented infections occurred in 5 patients with neutropenia. The response rate of 28% is better than that achieved with cisplatin alone and not dissimilar to the range of response for MVAC. Toxicities were less and tolerable. This regimen will need further evaluation.

A phase II trial of interferon-alpha and 5-fluorouracil in patients with advanced renal cell carcinoma. A Southwest Oncology Group study.

BACKGROUND: Renal cell carcinoma is a common neoplasm that is often refractory to treatment. It is occasionally responsive to immunomodulating agents including interferon-alpha, which enhances the effects of 5-fluorouracil upon cells. Combinations of these two drugs have been most frequently tested in patients with gastrointestinal cancers, with some promising results. Because interferon-alpha has activity for renal cell carcinoma, a trial of this combination in patients with this malignancy was undertaken. METHODS: The Southwest Oncology Group performed a Phase II clinical trial of the combination of 5-fluorouracil and interferon-alpha for recurrent or metastatic renal cell carcinoma. Eligibility criteria included no prior treatment with medications for cancer, a performance status of 2 or better, and bidimensionally measurable disease. The regimen studied consisted of 5-fluorouracil, 750 mg/M2/day, by continuous intravenous infusion on Days 1-5, and interferon-alpha-2b (Intron A), 5 x 10(6)U/M2/day, subcutaneously on Days 1, 3, and 5, repeated every 21 days. RESULTS: Forty eligible patients were treated; twenty of the 40 underwent a nephrectomy. The regimen was tolerable: 3 patients had Grade 4, and 17 had Grade 3 toxicity. There were 5 partial responses (13% with 95% confidence limits of 4-27%). Median progression free survival for all 40 patients was 4 months and median overall survival was 15 months from the time of registration. CONCLUSIONS: The combination of 5-fluorouracil and interferon-alpha given by this schedule, although tolerable and occasionally yielding responses, is not an improvement over existing therapies.

Oncocytic adenocarcinoma of minor salivary gland. An unusual glossal presentation of a minor salivary gland tumor.

A case of an unusual oncocytic variant of minor salivary gland adenocarcinoma presenting in the base of the tongue in a 79 year old male with a remote history of regional radiotherapy is presented. The tumor had a striking morphologic similarity to the more common granular cell tumor, with which it could have been easily confused, leading to significant misdiagnosis. The light microscopic, cytologic, immunohistochemical and electron microscopic features are presented, with a discussion of the differentiating features of this lesion compared to other more common benign and malignant glossal tumors.

Ondansetron for nausea and vomiting associated with moderately emetogenic cancer chemotherapy.

This multicenter, randomized, double-blind study compared the efficacy and tolerability of ondansetron 8 mg twice daily for 3 days with placebo in preventing nausea and vomiting in 81 patients receiving cyclophosphamide-doxorubicin-based chemotherapy. The first dose of study drug was administered 30 minutes before the initiation of chemotherapy. Patients received a rescue antiemetic if the investigator deemed it necessary or if the patient experienced more than two emetic episodes during the 3-day study. Sixty-one percent of patients treated with ondansetron compared with 6% of patients receiving placebo (P < 0.001) had no emetic episodes during the 3-day study. Among patients with at least one emetic episode, the mean time to emesis was 24 hours 18 minutes in the ondansetron group compared with 8 hours 1 minute in the placebo group (P < 0.001). In the intent-to-treat analysis, 78% of patients in the ondansetron group and 29% of patients in the placebo group completed the study with no need for rescue therapy. Clinical laboratory and adverse-event profiles were similar between groups. The most common adverse event was headache, occurring in 23% of ondansetron patients and 24% of placebo patients. This study is the first double-blind, placebo-controlled trial to demonstrate that ondansetron 8 mg twice daily is effective in the prevention of nausea and vomiting associated with cyclophosphamide-doxorubicin-based chemotherapy. The twice-daily regimen may encourage patient compliance and may be more cost-effective than regimens that need to be given three times daily.

Alternate disposition of tetrads in peripheral couplings of skeletal muscle.

The sarcoplasmic reticulum forms junctions with the surface membrane (peripheral couplings), which are structurally and functionally equivalent to the junctions between sarcoplasmic reticulum and transverse tubules (triads and dyads). Feet (ryanodine receptors, or sarcoplasmic reticulum calcium release channels) are disposed in arrays in the junctional sarcoplasmic reticulum membrane. Tetrads (groups of four dihydropyridine receptors, each called a unit) are disposed in ordered arrays in junctional domains of transverse tubules and surface membrane. We measured three parameters of tetrad arrays in peripheral couplings from three different species: (1) the centre-to-centre distances between tetrads (intertetrad spacing); (2) the angle between lines joining tetrad units and those joining the centres of tetrads (skew angle); (3) the centre-to-centre distance between tetrad units (intratetrad spacing). These measurements are compared with those predicted from models of feet and tetrad arrays. Intratetrad spacings and skew angles are consistent with an interaction of tetrads with alternate feet and with a location of tetrad units over feet subunits. The slightly larger size of the intratetrad spacing relative to the distance between feet subunits indicates that tetrads may be larger than feet, despite the fact that the molecular weight of DHPRs is less than that of feet subunits. This is offered as a possible explanation for the association of tetrads with alternate feet. Arrays of tetrads tend to be incomplete in images from freeze-fractures, due to lack of some of the units composing the tetrads.(ABSTRACT TRUNCATED AT 250 WORDS)

Evaluation of low dose continuous infusion 5-fluorouracil in patients with advanced and recurrent renal cell carcinoma. A Southwest Oncology Group Study.

BACKGROUND: The response rate of metastatic renal cell cancer to cytotoxic therapy over the last 10 years has been 5.6%. Low dose continuous 5-fluorouracil (5-FU) has demonstrated efficacy in other cytotoxic refractory tumors, such as pancreas, colorectal, and recurrent breast. The Southwest Oncology Group undertook a Phase II trial of low dose, continuous 5-FU in metastatic renal cell cancer. METHODS: Sixty-one patients were entered in the study to receive 300 mg 5-FU/m2/day for 7 days via a central venous catheter and external programmable pump. The pump was refilled every 7 days. Pyridoxine (50 mg, orally) was administered prophylactically three times a day. RESULTS: A response of 5.2% (one complete response [CR] and two partial responses [PRs]) was achieved. The overall survival was 12 months. The duration of the CR is more than 30 months. Both PRs lasted 6 months. No survival advantage was noted with either prior nephrectomy or biologic therapy. The majority of toxicities were Grade 2: anemia, anorexia, diarrhea, nausea/vomiting, and stomatitis. No toxic deaths occurred. CONCLUSION: Low dose, continuous 5-FU demonstrated minimal activity in metastatic renal cancer.

A randomized, double-blind comparison of intravenous ondansetron alone and in combination with intravenous dexamethasone in the prevention of high-dose cisplatin-induced emesis.

PURPOSE: This study compares the efficacy and safety of ondansetron alone with that of ondansetron plus dexamethasone in the prevention of emesis induced by high-dose cisplatin (> or = 100 mg/m2). PATIENTS AND METHODS: This multicenter study used a randomized, double-blind, parallel-group design. Chemotherapy-naive patients were randomized to receive intravenous (IV) ondansetron (Zofran, Cerenex Pharmaceuticals, Research Triangle Park, NC) 0.15 mg/kg for three doses every 4 hours beginning 30 minutes before cisplatin administration either alone or in combination with dexamethasone 20 mg administered 45 minutes before cisplatin. Cisplatin (> or = 100 mg/m2) was administered as a single infusion (< or = 3 hours). Patients were monitored for emetic episodes (EEs), adverse events, and laboratory safety parameters for 24 hours after cisplatin administration. RESULTS: A total of 275 patients were enrolled. Of these, 245 were assessable for efficacy. Patients who received ondansetron plus dexamethasone had a higher complete antiemetic response rate (61% v 46%, P = .02) and less nausea (posttreatment visual analog scale mean 18.2 v 32.8, P < .001) than did those who received ondansetron alone. The time to the first EE was longer for patients in the group that received ondansetron plus dexamethasone (P = .005). Headache (12%), diarrhea (2%), and abdominal colic (1%) were the most common antiemetic-related adverse events reported. The incidence of adverse events was similar between the treatment groups. CONCLUSION: IV ondansetron in combination with dexamethasone is safe and more effective than ondansetron alone in the prevention of emesis induced by high-dose cisplatin.

Comparison of a quadroma and its parent hybridomas in fed batch culture.

A quadroma (#22 x 63), formed by the fusion of two hybridomas, and its parent hybridomas (#22 and FMC 63) were each grown in fed batch cultures in order to examine the change in antibody productivity over time of the quadroma compared to its parent hybridomas. The growth rate, glucose uptake rate and lactate production rate of the quadroma were found to be intermediate between those of its parent cells of origin. The specific antibody productivity and internal antibody content of the quadroma followed the same decreasing trends over time as those seen in both parent hybridomas. Losses in specific antibody production rate and antibody content, however, occurred at a faster rate for the quadroma than for either of its parent hybridomas. Although the growth of a non-producing subpopulation is presumed to account for the drop in antibody production, there was no direct correlation between the percentage of high antibody containing cells, as determined by flow cytometry, and the specific antibody production rate.