Objectives:Cancer patients routinely exhibit dysfunctional circadian organization. Indeed, a dysfunctional circadian organization is a hallmark of advanced cancer. A cohort of advanced cancer patients undergoing chemotherapy was recruited to investigate whether manipulating exposure to blue light could restore or ameliorate their circadian organization.Methods:Thirty advanced metastatic cancer patients participated in a randomized crossover trial to evaluate whether blue light-blocking night-simulating eyeglasses could ameliorate a disrupted circadian organization better than sham eyeglasses. Circadian organization was evaluated by actigraphy and patients’ self-reports of sleep, fatigue, and quality of life. Kruskal–Wallis tests compared patients’ outcomes in circadian organization with a cohort of non-cancer, disease-free individuals with normal sleep as a negative control, and with advanced cancer patients with disrupted circadian organization as a positive control. Quality-of-life outcomes of the patients were compared with population-based controls (negative controls) and with cohorts of advanced cancer patients (positive controls).Results:Actigraphy measurements, self-reported sleep, fatigue levels, and quality-of-life outcomes of trial participants were similar to those of negative controls with a normal circadian organization, in spite of the trial patients’ concurrent chemotherapy. Night-simulating glasses did not improve circadian organization. The 24-h correlation of day-to-day rhythms of rest and activity was 0.455 for the experimental eyeglasses and 0.476 for the sham eyeglasses (p = 0.258). Actigraphic and patient-reported outcomes compared favorably to outcomes of positive controls.Conclusion:The circadian organization of patients in this study unexpectedly resembled that of healthy controls and was better than comparison populations with disrupted circadian organization. The study clinic implements chronomodulated chemotherapy and a systematic, supportive integrative treatment protocol. Results suggest a need for further research on interventions for circadian rhythm. Although the study intervention did not benefit the participants, this work highlights the value of supporting circadian time structure in advanced cancer patients.

Backgroundα-tocopherol (AT) and γ-tocotrienol (GT3) are vitamin E isoforms considered to have potential chemopreventive properties. AT has been widely studied in vitro and in clinical trials with mixed results. The latest clinical study (SELECT trial) tested AT in prostate cancer patients, determined that AT provided no benefit, and could promote cancer. Conversely, GT3 has shown antineoplastic properties in several in vitro studies, with no clinical studies published to date. GT3 causes apoptosis via upregulation of the JNK pathway; however, inhibition results in a partial block of cell death. We compared side by side the mechanistic differences in these cells in response to AT and GT3.MethodsThe effects of GT3 and AT were studied on androgen sensitive LNCaP and androgen independent PC-3 prostate cancer cells. Their cytotoxic effects were analyzed via MTT and confirmed by metabolic assays measuring ATP. Cellular pathways were studied by immunoblot. Quantitative analysis and the determination of relationships between cell signaling events were analyzed for both agents tested. Non-cancerous prostate RWPE-1 cells were also included as a control.ResultsThe RAF/RAS/ERK pathway was significantly activated by GT3 in LNCaP and PC-3 cells but not by AT. This activation is essential for the apoptotic affect by GT3 as demonstrated the complete inhibition of apoptosis by MEK1 inhibitor U0126. Phospho-c-JUN was upregulated by GT3 but not AT. No changes were observed on AKT for either agent, and no release of cytochrome c into the cytoplasm was detected. Caspases 9 and 3 were efficiently activated by GT3 on both cell lines irrespective of androgen sensitivity, but not in cells dosed with AT. Cell viability of non-cancerous RWPE-1 cells was affected neither by GT3 nor AT.Conclusionsc-JUN is a recognized master regulator of apoptosis as shown previously in prostate cancer. However, the mechanism of action of GT3 in these cells also include a significant activation of ERK which is essential for the apoptotic effect of GT3. The activation of both, ERK and c-JUN, is required for apoptosis and may suggest a relevant step in ensuring circumvention of mechanisms of resistance related to the constitutive activation of MEK1.

5-fluorouracil (5-FU) and its prodrug capecitabine are frequently prescribed in oncology. While usually well tolerated, toxicity can be severe, and even life-threatening. A dihydropyrimidine dehydrogenase (DPD) deficiency can cause severe toxicity. Current testing for DPD deficiency does not meet the criteria for a routine screening test prior to 5-FU therapy. A case study of a fatality secondary to capecitabine toxicity is reviewed and literature is examined regarding general screening for DPD deficiency.

Pulmonary hypertension is a life-threatening illness with debilitating physical and emotional consequences. The progression of this devastating disease is characterized by a continuous increase in pulmonary vascular resistance, which results in elevated pulmonary artery pressure and leads to right heart failure. Treatment is focused on targeting the underlying complex etiology via the endothelin, prostacyclin, and nitric oxide (NO) pathways. Emergence of new treatments over the past 2 decades has led to improvement in the functional status and time to clinical worsening. Even with recent advances, outcomes remain suboptimal. Phosphodiesterase-5 (PDE-5) inhibitors, such as sildenafil, were approved for treatment of pulmonary arterial hypertension (PAH) by the Food and Drug Administration (FDA) in 2005, which holds promise in improving quality of life and therefore making this class of medications effective palliative therapy agents. In this review, we summarize the emergence of sildenafil as a treatment for PAH and its role as palliative therapy.

JM is a 32-year-old primagravida with polycystic ovary disease. She had extreme difficulty conceiving and was started on clomiphene 6 months ago by her fertility specialist. After doubling the dose on the sixth cycle, she successfully became pregnant. On her second prenatal visit at 12 weeks gestation, an ovarian cyst was detected. Ultrasound showed a complex ovarian mass with nodules on the bowel and abdominal wall. There was mild-to-moderate peritoneal fluid. Cytology showed adenocarcinoma of ovarian origin. Further workup demonstrated advanced stage III epithelial ovarian cancer. JM was referred to GYN-oncology who felt pregnancy-sparing debulking was not an option. The oncologist recommended termination of pregnancy due to the risks of delaying chemotherapy. JM refused, citing her fertility difficulties in the past and her desire to carry the pregnancy to term "even if it kills me." She tells the oncologist she cannot bear the thought of terminating her pregnancy under any circumstances. The oncologist wants to comply with her wishes but feels the patient is making a choice that would result in harm to herself. The oncology team requests an ethics consult.

TPS716 Background: HER2 has been shown to be a validated therapeutic target for the treatment of mCRC. Preclinical and clinical evidence supports the use of HER2-targeted agents in each of these mCRC cohorts. In HERACLES, treatment–refractory, KRAS exon 2 (codons 12 and 13) WT, HER2 amp mCRC pts were treated with T and lapatinib (L). Objective response rate (CR or PR) was 8/27 and disease control rate (CR, PR, and SD > 16 wks) was 16/27. Duration of response ranged from 24-94+ wks. Anecdotal reports have shown activity of N in HER2 mts from several cancer types. In mCRC PDX models with qualifying HER2 mts, T plus N is more active than either drug alone. In quad WT, HER2 non-amp PDX models, C plus TKI resulted in major tumor regressions not seen with C monotherapy. In NSABP FC-7, a trial of C + N in cetuximab refractory pts, HER2 amp was observed in 2/23 primary tissue samples; after C exposure, HER2 amp was seen in 5/17 samples, presumably signal upregulation under selective pressure of C. HER2 amp was concordant in tissue (CISH) and blood using cfDNA. Methods: This multi-center 3-cohort phase II trial is currently enrolling pts (total planned N = 35). Pts with quad WT, HER2 amp (n = 15) with prior anti-EGFR therapy and/or HER2 mt mCRC (n = 5) will receive T 4 mg/kg iv loading dose followed by 2 mg/kg/wk and N 240 mg po daily (Arm 1). Pts with quad WT, HER2 non-amp (n = 15) with no prior anti-EGFR therapy will receive C 400 mg/m2 iv loading dose followed by 250 mg/m2/wk, and N 240 mg (Arm 2). Specific pt eligibility for quad WT and HER2 status are defined below: Arm 1: HER2 amp confirmed in blood by Guardant360 assay, and prior treatment with C or panitumumab (P). HER2 mt (with qualifying mt) with or without prior treatment with C or P. Arm 2: HER2 non-amp or HER2 amp and no prior therapy with C or P. The primary aim is 6-mos progression-free survival for each cohort. Secondary aims: response rates and toxicity. Exploratory aims: genetic and molecular analyses. Specific drug combinations will be evaluated in PDX models. NCT03457896. Support: Puma Biotechnology, Inc.; NSABP Foundation, Inc. Clinical trial information: NCT03457896.

Often, advanced practitioners must give clinical presentations. Public speaking, which is a major fear for most individuals, is a developed skill. Giving an oral presentation is a good way to demonstrate work, knowledge base, and expertise. Giving an effective presentation can help obtain recognition of skills and proficiency as an advanced practitioner or expert in the field. This paper will highlight skills and techniques that can help to improve presentation style and the ability to connect with an audience.

An alternative analgesic to morphine is methadone, which is used to control chronic pain and is used in opioid rehabilitation treatment programs due to methadone having a long half-life and being relatively inexpensive as compared to extended-release forms of morphine. Despite its benefits, methadone accumulates in adipose tissue due to being lipophilic, binds strongly to plasma proteins, and is metabolized in the liver by the cytochrome P450 system causing methadone levels to be variable and subject to influence according to the individual body compositions and concurrent use of cytochrome P450 inhibitors. In addition to methadone being able to cause both respiratory and central nervous system depression, methadone can also prolong the QT interval and cause potentially life-threatening arrhythmias including torsades de pointes. The susceptibility of unintentional overdosing of methadone due to its varied pharmacologic properties and potentially fatal induction of arrhythmias may cause the risks of methadone use to outweigh its benefits and therefore must be closely monitored.

e15622Background: National guidelines (NCCN 2016) recommend profiling for microsatellite instability (MSI) and mismatch repair (MMR) for all patients (pts) with colon cancer. Evaluations may identi...