Phase 1/2 Dose Escalating Study of Twice-Monthly Pemetrexed and Gemcitabine in Patients with Advanced Cancer and Non-small Cell Lung Cancer

IntroductionPemetrexed is synergistic with gemcitabine in preclinical models of non-small cell lung cancer (NSCLC). The optimal dose and utility of gemcitabine and pemetrexed was evaluated in a dose-escalating study.MethodsThe phase 1 study included patients with advanced tumors, whereas the phase 2 study included patients with locally advanced or metastatic NSCLC. Gemcitabine was infused over 30 minutes, followed by pemetrexed administered over 10 minutes on day 1 of a 14-day cycle. Treatment continued for 12 cycles or until disease progression. All patients received folic acid, Vitamin B12, and steroid prophylaxis.ResultsMaximum tolerated dose was gemcitabine 1500 mg/m2, followed by pemetrexed 500 mg/m2. Fifty-three patients (29 male, 24 female) were enrolled in the phase 2 study. Response rate was 20.8% (95% CI: 0.108–0.341), and the clinical benefit rate (CR + PR + SD) was 64.2%. Median time to disease progression was 4.6 months (95% CI: 2.79–6.18), median survival was 10.1 month (95% CI: 5.95–14.09, censorship = 20.75%), and 1-year survival was 41.0%. Common grade 3 or 4 adverse events (% of patients) were neutropenia (28.3%), fatigue (22.6%), and febrile neutropenia (9.4%).ConclusionsTwice-monthly gemcitabine and pemetrexed was well tolerated, with overall survival and clinical benefit indicating disease activity in NSCLC patients

Misdiagnosis of narcolepsy

BACKGROUND: Narcolepsy is a chronic primary sleep disorder, characterized by excessive daytime sleepiness and sleep dysfunction with or without cataplexy. Narcolepsy is uncommon, with a low prevalence rate which makes it difficult to diagnose definitively without a complex series of tests and a detailed history. The aim of this study was to review patients referred to a tertiary sleep centre who had been labelled with a diagnosis of narcolepsy prior to referral in order to assess if the diagnosis was accurate, and if not, to determine the cause of diagnostic misattribution. METHODS: All patients seen at a sleep centre from 2007–2013 (n = 551) who underwent detailed objective testing including an MSLT PSG, as well as wearing an actigraphy watch and completing a sleep diary for 2 weeks, were assessed for a pre-referral and final diagnosis of narcolepsy. RESULTS: Of the 41 directly referred patients with a diagnostic label of narcolepsy, 19 (46 %) were subsequently confirmed to have narcolepsy on objective testing and assessment by a sleep physician using ICSD-2 criteria. CONCLUSIONS: The diagnosis of narcolepsy was incorrectly attributed to almost 50 % of patients labelled with a diagnosis of narcolepsy who were referred for further opinion by a variety of specialists and generalists. Accurate diagnosis of narcolepsy is critical for many reasons, such as the impact it has on quality of life, driving, employment, insurance and pregnancy in women as well as medication management

Efficient derivation of NPCs, spinal motor neurons and midbrain dopaminergic neurons from hESCs at 3% oxygen

This protocol has been designed to generate neural precursor cells (NPCs) from human embryonic stem cells (hESCs) using a physiological oxygen (O(2)) level of 3% and chemically defined conditions. The first stage involves suspension culture of hESC colonies at 3% O(2), where they acquire a neuroepithelial identity over two weeks. This timescale is comparable to that at 20% O(2), but survival is enhanced. Sequential application of retinoic acid (RA) and purmorphamine (PM), from day 14 to 28, directs differentiation towards spinal motor neurons. Alternatively, addition of FGF-8 and PM generates midbrain dopaminergic neurons. OLIG2 induction in motor neuron precursors is 2-fold greater than at 20% O(2), whereas EN1 is 5-fold enhanced. 3% NPCs can be differentiated into all three neural lineages, and such cultures can be maintained long-term in the absence of neurotrophins. The ability to generate defined cell types at 3% O(2) should represent a significant advance for in vitro disease modelling and potentially cell-based therapies

Phase i trial of axitinib combined with platinum doublets in patients with advanced non-small cell lung cancer and other solid tumours

BACKGROUND: This phase I dose-finding trial evaluated safety, efficacy and pharmacokinetics of axitinib, a potent and selective secondgeneration inhibitor of vascular endothelial growth factor receptors, combined with platinum doublets in patients with advanced non-small cell lung cancer (NSCLC) and other solid tumours. METHODS: In all, 49 patients received axitinib 5mg twice daily (b.i.d.) with paclitaxel/carboplatin or gemcitabine/cisplatin in 3-week cycles. Following determination of the maximum tolerated dose, a squamous cell NSCLC expansion cohort was enroled and received axitinib 5mg b.i.d. with paclitaxel/carboplatin. RESULTS: Two patients experienced dose-limiting toxicities: febrile neutropenia (n¼1) in the paclitaxel/carboplatin cohort and fatigue (n¼1) in the gemcitabine/cisplatin cohort. Common nonhaematologic treatment-related adverse events were hypertension (36.7%), diarrhoea (34.7%) and fatigue (28.6%). No gradeX3 haemoptysis occurred among 12 patients with squamous cell NSCLC. The objective response rate was 37.0% for patients receiving axitinib/paclitaxel/carboplatin (n¼27) and 23.8% for patients receiving axitinib/gemcitabine/cisplatin (n¼21). Pharmacokinetics of axitinib and chemotherapeutic agents were similar when administered alone or in combination. CONCLUSION: Axitinib 5mg b.i.d. may be combined with standard paclitaxel/carboplatin or gemcitabine/cisplatin regimens without evidence of overt drug–drug interactions. Both combinations demonstrated clinical efficacy and were well tolerated.This study was sponsored by Pfizer Inc. Support was provided in part by National Institutes of Health grant P30 CA006927 to the Fox Chase Cancer Center. We thank the patients who participated in this study and the physicians who referred them, as well as the study coordinators and data managers, Shelley Mayfield and Carol Martins at Pfizer Inc. for support of the study conduct, and Gamal ElSawah, Pfizer Medical Affairs, for his review of the manuscript. Medical writing support was provided by Joanna Bloom, of UBC Scientific Solutions (Southport, CT, USA) and Christine Arris at ACUMED (Tytherington, UK) and was funded by Pfizer In

Swallowing, nutrition and patient-rated functional outcomes at 6 months following two non-surgical treatments for T1-T3 oropharyngeal cancer

Altered fractionation radiotherapy with concomitant boost (AFRT-CB) may be considered an alternative treatment for patients not appropriate for chemoradiation (CRT). As functional outcomes following AFRT-CB have been minimally reported, this exploratory paper describes the outcomes of patients managed with AFRT-CB or CRT at 6 months post-treatment

Physiological changes to the swallowing mechanism following (Chemo)radiotherapy for head and neck cancer: a systematic review

Emerging research suggests that preventative swallowing rehabilitation, undertaken before or during (chemo)radiotherapy ([C]RT), can significantly improve early swallowing outcomes for head and neck cancer (HNC) patients. However, these treatment protocols are highly variable. Determining specific physiological swallowing parameters that are most likely to be impacted post-(C)RT would assist in refining clear targets for preventative rehabilitation. Therefore, this systematic review (1) examined the frequency and prevalence of physiological swallowing deficits observed post-(C)RT for HNC, and (2) determined the patterns of prevalence of these key physiological deficits over time post-treatment. Online databases were searched for relevant papers published between January 1998 and March 2013. A total of 153 papers were identified and appraised for methodological quality and suitability based on exclusionary criteria. Ultimately, 19 publications met the study’s inclusion criteria. Collation of reported prevalence of physiological swallowing deficits revealed reduced laryngeal excursion, base-of-tongue (BOT) dysfunction, reduced pharyngeal contraction, and impaired epiglottic movement as most frequently reported. BOT dysfunction and impaired epiglottic movement showed a collective prevalence of over 75 % in the majority of patient cohorts, whilst reduced laryngeal elevation and pharyngeal contraction had a prevalence of over 50 %. Subanalysis suggested a trend that the prevalence of these key deficits is dynamic although persistent over time. These findings can be used by clinicians to inform preventative intervention and support the use of specific, evidence-based therapy tasks explicitly selected to target the highly prevalent deficits post-(C)RT for HNC

Wake Up and Talk with Me! In-the-Field Study of an Autonomous Interactive Wake Up Robot

12th International Conference, ICSR 2020, Golden, CO, USA, November 14–18, 2020In this paper, we present a robot that is designed to smoothly wake up a user in the morning. We created an autonomous interactive wake up robot that implements a wake up behavior that was selected through preliminary experiments. We conducted a user study to test the interactive robot and compared it to a baseline robot that behaves like a conventional alarm clock. We recruited 22 participants that agreed to bring the robot to their home and test it for two consecutive nights. The participants felt significantly less sleepy after waking up with the interactive robot, and reported significantly more intention to use the interactive robot

A prospective investigation of swallowing, nutrition, and patient-rated functional impact following altered fractionation radiotherapy with concomitant boost for oropharyngeal cancer

Altered fractionation radiotherapy for head and neck cancer has been associated with improved locoregional control, overall survival, and heightened toxicity compared with conventional treatment. Swallowing, nutrition, and patient-perceived function for altered fractionation radiotherapy with concomitant boost (AFRT-CB) for T1–T3 oropharyngeal squamous cell carcinoma (SCC) have not been previously reported. Fourteen consecutive patients treated with AFRT-CB for oropharyngeal SCC were recruited from November 2006 to August 2009 in a tertiary hospital in Brisbane, Australia. Swallowing, nutrition, and patient-perceived functional impact assessments were conducted pretreatment, at 4–6 weeks post-treatment, and at 6 months post-treatment. Deterioration from pretreatment to 4–6 weeks post-treatment in swallowing, nutrition, and functional impact was evident, likely due to the heightened toxicity associated with AFRT-CB. There was significant improvement at 6 months post-treatment in functional swallowing, nutritional status, patient-perceived swallowing, and overall function, consistent with recovery from acute toxicity. However, weight and patient perception of physical function and side effects remained significantly worse than pretreatment scores. The ongoing deficits related to weight and patient-perceived outcomes at 6 months revealed that this treatment has a long-term impact on function possibly related to the chronic effects of AFRT-CB

Definition of Healthy Ranges for Alanine Aminotransferase Levels: A 2021 Update

The changing epidemiology of liver disease, and modifications in the recommended analytical methodology call for a re-evaluation of the upper reference limits (URLs) of alanine aminotransferase (ALT) levels. Using the same ap- proach consolidated 20 years ago to define the healthy population, we defined the URL for the newly recommended International Federation of Clinical Chemistry (IFCC) standardized test. In a cross-sectional study, we examined 21,296 apparently healthy blood donors (age 18-65 years) and calculated the sex-specific URL by the 95th percentile in indi- viduals without risk factors for liver disease. These were tested for the ability to predict liver damage in a subset of 745 participants with dysmetabolism, in an independent cohort of 977 unselected donors, and in 899 patients with chronic liver disease. ALT levels were measured by the IFCC test. Male sex, body mass index, glucose, lipids, ferritin, hyper- tension, and younger age were independent ALT predictors (P < 0.001). Updated URLs were identified at 42/30 U/L in males/females, approximately 30% lower than those currently recommended by the IFCC. Due to improved sensitiv- ity, they conferred the ability to detect steatosis and significant fibrosis in individuals with dysmetabolism (odds ratio [OR] = 2.31, range 1.40-3.80, P = 0.001; and OR = 3.35, range 1.19-9.42, P = 0.021; respectively), although with a limited accuracy, and significant fibrosis in unselected donors (OR = 2.32, 1.02-5.31, P = 0.045). Updated URLs had a moderate to high accuracy to discriminate liver conditions (area under the receiver operating characteristic curve = 0.81, range 0.78-0.91). Conclusion: Updated URLs by the IFCC method were lower than those calculated in initial studies, but higher than those in use with the recommended old, nonstandardized method, and were able to better predict liver disease. The limited awareness that different techniques are still in use should be regarded as a possible source of medical errors