Cardiotoxicity of BTK inhibitors: ibrutinib and beyond.

INTRODUCTION: The development of Brutons Tyrosine Kinase (BTK) inhibitors has transformed the treatment of B-cell malignancies and other non-malignant conditions. Management of the unique cardiotoxic profile of these agents requires prompt recognition and a multi-disciplinary approach. AREAS COVERED: The increasing indications and addition of newer agents to clinical practice and emergence of BTK inhibitor-related cardiac adverse events have complicated the management decisions for utilization of this class of therapy. We review the incidence, mechanisms, and management approaches for BTK inhibitor-related atrial fibrillation, hypertension, and ventricular arrhythmias. EXPERT OPINION: The newer BTK inhibitor acalabrutinib represents a new standard of care in front-line chronic lymphocytic leukemia (CLL) given the results of the ELEVATE-RR trial demonstrating comparable efficacy and a more favorable toxicity profile especially with regard to cardiac adverse events as compared to ibrutinib. Often not recognized by clinicians, BTK inhibitor-induced hypertension is common and can be severe, requiring prompt recognition and initiation or adjustment of anti-hypertensive medications to prevent major adverse cardiac outcomes. Novel BTK inhibitors in development are being designed to overcome the patterns of resistance from first-generation agents and to minimize off-target kinase activity, with promising toxicity profiles in early trials.

Addition of price transparency to an education and feedback intervention reduces utilization of inpatient echocardiography by resident physicians.

Previous studies have demonstrated the impact of appropriate use criteria (AUC) education and feedback interventions in reducing unnecessary ordering of transthoracic echocardiography (TTE) by trainees. To our knowledge, no study has evaluated the impact of the addition of price transparency to this education and feedback model on TTE utilization by resident physicians. We performed an education and feedback quality improvement initiative combining charge transparency data with information on AUC. We hypothesized that the initiative would reduce the number of complete TTE ordered and increase the number of limited TTE ordered, anticipating there would be substitution of limited for complete studies. Residents rotating on inpatient teaching cardiology ward teams received education on AUC for TTE, indications for limited TTE, and hospital charges for TTE. Feedback was provided on the quantity and charges for complete and limited TTE ordered by each team. We analyzed the effects of the intervention using a linear mixed effects regression model to adjust for potential confounders. The post-intervention weeks showed a reduction of 4.6 complete TTE orders per 100 patients from previous weekly baseline of 31.3 complete TTE orders per 100 patients (p value = 0.012). Charges for complete TTE decreased $122 from baseline of $980 per patient (p value = 0.040) on a per-week basis. Secondarily, there was no statistically significant change in limited TTE ordering during the intervention period. This initiative shows the feasibility of a house staff-driven charge transparency and education/feedback initiative that decreased medical residents' ordering of inpatient TTE.

A retrospective cost analysis of the frequency and cost of transfusion premedications.

BACKGROUND: Acetaminophen and diphenhydramine are routinely administered to prevent febrile non-hemolytic and allergic blood transfusion reactions despite multiple randomized controlled trials demonstrating that this practice lacks efficacy. As a result, patients are exposed to the adverse effects of these medications and their financial burdens with no expected benefit. The aim of this study was to quantify the frequency and cost of transfusion premedications in patients with acute myeloid leukemia (AML). STUDY DESIGN AND METHODS: This was a retrospective study of patients with AML admitted to Vanderbilt University Medical Center (VUMC) for induction chemotherapy between January 2008 and December 2016. Data were collected on the number of platelet and packed red blood cell (PRBC) transfusions each patient received during the initial inpatient encounter for AML, as well as on the administration of premedications prior to each transfusion. RESULTS: During the 9-year study period, 948 AML patients received a total of 19,820 transfusions. Of these, 30% were preceded by oral diphenhydramine, 8% by intravenous diphenhydramine, and 39% by oral acetaminophen. The percentage of patients that received a transfusion preceded by a premedication increased over the study period (p = 0.03), as did the percentage of transfusions preceded by a premedication (p = 0.02). The total unadjusted cost of pre-transfusion medications to the institution during the study period was $50,309.77, or $52.67 per patient with AML. The cost of premedications per patient did not increase over the study period (p = .45). CONCLUSIONS: Routine transfusion premedication administration is common in AML patients and not well-supported by available evidence.

Experimentally generated randomness certified by the impossibility of superluminal signals.

From dice to modern electronic circuits, there have been many attempts to build better devices to generate random numbers. Randomness is fundamental to security and cryptographic systems and to safeguarding privacy. A key challenge with random-number generators is that it is hard to ensure that their outputs are unpredictable1-3. For a random-number generator based on a physical process, such as a noisy classical system or an elementary quantum measurement, a detailed model that describes the underlying physics is necessary to assert unpredictability. Imperfections in the model compromise the integrity of the device. However, it is possible to exploit the phenomenon of quantum non-locality with a loophole-free Bell test to build a random-number generator that can produce output that is unpredictable to any adversary that is limited only by general physical principles, such as special relativity1-11. With recent technological developments, it is now possible to carry out such a loophole-free Bell test12-14,22. Here we present certified randomness obtained from a photonic Bell experiment and extract 1,024 random bits that are uniformly distributed to within 10-12. These random bits could not have been predicted according to any physical theory that prohibits faster-than-light (superluminal) signalling and that allows independent measurement choices. To certify and quantify the randomness, we describe a protocol that is optimized for devices that are characterized by a low per-trial violation of Bell inequalities. Future random-number generators based on loophole-free Bell tests may have a role in increasing the security and trust of our cryptographic systems and infrastructure.

Advanced active quenching circuit for ultra-fast quantum cryptography.

Commercial photon-counting modules based on actively quenched solid-state avalanche photodiode sensors are used in a wide variety of applications. Manufacturers characterize their detectors by specifying a small set of parameters, such as detection efficiency, dead time, dark counts rate, afterpulsing probability and single-photon arrival-time resolution (jitter). However, they usually do not specify the range of conditions over which these parameters are constant or present a sufficient description of the characterization process. In this work, we perform a few novel tests on two commercial detectors and identify an additional set of imperfections that must be specified to sufficiently characterize their behavior. These include rate-dependence of the dead time and jitter, detection delay shift, and "twilighting". We find that these additional non-ideal behaviors can lead to unexpected effects or strong deterioration of the performance of a system using these devices. We explain their origin by an in-depth analysis of the active quenching process. To mitigate the effects of these imperfections, a custom-built detection system is designed using a novel active quenching circuit. Its performance is compared against two commercial detectors in a fast quantum key distribution system with hyper-entangled photons and a random number generator.

Strong Loophole-Free Test of Local Realism.

We present a loophole-free violation of local realism using entangled photon pairs. We ensure that all relevant events in our Bell test are spacelike separated by placing the parties far enough apart and by using fast random number generators and high-speed polarization measurements. A high-quality polarization-entangled source of photons, combined with high-efficiency, low-noise, single-photon detectors, allows us to make measurements without requiring any fair-sampling assumptions. Using a hypothesis test, we compute p values as small as 5.9×10^{-9} for our Bell violation while maintaining the spacelike separation of our events. We estimate the degree to which a local realistic system could predict our measurement choices. Accounting for this predictability, our smallest adjusted p value is 2.3×10^{-7}. We therefore reject the hypothesis that local realism governs our experiment.

A double-blind, placebo-controlled trial of a topical treatment for chemotherapy-induced peripheral neuropathy: NCCTG trial N06CA.

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is a troublesome chronic symptom that has no proven pharmacologic treatment. The purpose of this double-blind randomized placebo-controlled trial was to evaluate a novel compounded topical gel for this problem. METHODS: Patients with CIPN were randomized to baclofen 10 mg, amitriptyline HCL 40 mg, and ketamine 20 mg in a pluronic lecithin organogel (BAK-PLO) versus placebo (PLO) to determine its effect on numbness, tingling, pain, and function. The primary endpoint was the baseline-adjusted sensory subscale of the EORTC QLQ-CIPN20, at 4 weeks. RESULTS: Data in 208 patients reveal a trend for improvement that is greater in the BAK-PLO arm over placebo in both the sensory (p = 0.053) and motor subscales (p = 0.021). The greatest improvements were related to the symptoms of tingling, cramping, and shooting/burning pain in the hands as well as difficulty in holding a pen. There were no undesirable toxicities associated with the BAK-PLO and no evidence of systemic toxicity. CONCLUSION: Topical treatment with BAK-PLO appears to somewhat improve symptoms of CIPN. This topical gel was well tolerated, without evident systemic toxicity. Further research is needed with increased doses to better clarify the clinical role of this treatment in CIPN.

Pilot study of Panax quinquefolius (American ginseng) to improve cancer-related fatigue: a randomized, double-blind, dose-finding evaluation: NCCTG trial N03CA.

PURPOSE: This pilot trial sought to investigate whether any of three doses of American ginseng (Panax quinquefolius) might help cancer-related fatigue. A secondary aim was to evaluate toxicity. METHODS: Eligible adults with cancer were randomized in a double-blind manner, to receive American ginseng in doses of 750, 1,000, or 2,000 mg/day or placebo given in twice daily dosing over 8 weeks. Outcome measures included the Brief Fatigue Inventory, vitality subscale of the Medical Outcome Scale Short Form-36 (SF-36), and the Global Impression of Benefit Scale at 4 and 8 weeks. RESULTS: Two hundred ninety patients were accrued to this trial. Nonsignificant trends for all outcomes were seen in favor of the 1,000- and 2,000-mg/day doses of American ginseng. Area under the curve analysis of activity interference from the Brief Fatigue Inventory was 460-467 in the placebo group and 750 mg/day group versus 480-551 in the 1,000- and 2,000-mg/day arms, respectively. Change from baseline in the vitality subscale of the SF-36 was 7.3-7.8 in the placebo and the 750-mg/day arm, versus 10.5-14.6 in the 1,000- and 2,000-mg/day arms. Over twice as many patients on ginseng perceived a benefit and were satisfied with treatment over those on placebo. There were no significant differences in any measured toxicities between any of the arms. CONCLUSION: There appears to be some activity and tolerable toxicity at 1,000-2,000 mg/day doses of American ginseng with regard to cancer-related fatigue. Thus, further study of American ginseng is warranted.

Use of a lidocaine patch in the management of postsurgical neuropathic pain in patients with cancer: a phase III double-blind crossover study (N01CB).

OBJECTIVE: Current therapies often have limited efficacy and untenable side effects when used to treat persistent incisional pain following cancer-related surgery. Lidocaine patches reduce neuropathic pain from herpes zoster but their benefits for persistent cancer-related postsurgical incisional pain remain unclear. STUDY DESIGN: Multicenter, double-blind, randomized, two-period crossover trial. MATERIALS AND METHODS: Twenty-eight cancer patients with postsurgical incisional pain were randomly assigned to receive either lidocaine patches followed by placebo patches or the reverse. Each study period lasted 4 weeks. Patches were applied daily upon waking and left in place for a maximum of 18 h. The primary outcome measure, an 11-point pain intensity rating scale, was administered weekly. Secondary outcomes were administered weekly (Brief Pain Inventory-Short Form(BPI-SF), Subject Global Impression of Change) and at the end of each study period (Short Form-Magill Pain Questionnaire, Linear Analogue Self Assessment Scale, Neuropathy Pain Scale, Pain Catastrophizing Scale, Profile of Mood States Short Form). RESULTS: Twenty-one patients completed the first period and 18 completed their crossover second phase. No significant intergroup differences were detected in pain intensity ratings. Few secondary end points were significantly different when subjects used the lidocaine versus placebo patches. BPI-SF interference scores were lower in patients using the lidocaine patch during the first study period, including several scores that achieved statistical significance, general activity (p = 0.02), work (p = 0.04), and relations with others (p = 0.02). CONCLUSION: Lidocaine patch use did not significantly reduce pain intensity ratings or the majority of related secondary end points in cancer patients with persistent incisional pain.

Pilot evaluation of paroxetine for treating hot flashes in men.

OBJECTIVE: To provide prospective information on the potential utility of paroxetine for treating hot flashes In men receiving androgen ablation therapy for prostate cancer. PATIENTS AND METHODS: Men with symptomatic androgen ablation therapy-related hot flashes were entered into this clinical trial between August 2001 and October 2003. After a baseline week of documentation of the frequency of hot flashes, patients were assigned to receive paroxetine; the initial dosage was 12.5 mg/d, and it was increased to 37.5 mg/d over the ensuing 4 weeks. RESULTS: Of the 24 patients in whom medication was initiated, 18 completed the 5-week study. In these patients, the median frequency of hot flashes decreased from 6.2 per day during the baseline week to 2.5 per day during the last study week. Hot flash scores (frequency x mean severity) during the same period decreased from 10.6 per day to 3.0 per day. Overall, paroxetine was well tolerated by most patients. CONCLUSION: The results from this trial suggest that paroxetine Is an effective agent for diminishing hot flashes in men receiving androgen ablation therapy.

Pilot evaluation of mirtazapine for the treatment of hot flashes.

This prospective, single-arm, pilot clinical trial, developed to evaluate the efficacy and tolerability of mirtazapine for alleviating hot flashes, was conducted between May 2001 and January 2002. Patients' baseline characteristics were collected during the first week of the study. At the beginning of the second week, patients were started on mirtazapine at a dose of 7.5 mg at bedtime. The dose of mirtazapine was then increased to 15 mg at week 3 and to 30 mg at week 4. For week 5, patients could choose whether to take 15 mg/d or 30 mg/d. Data were obtained primarily from patient-completed questionnaires. Data from 22 evaluable women were available. For the 16 patients who completed the study, the median reductions in total daily hot flashes and weekly hot-flash scores from their baselines were 52.5% and 59.5%, respectively. Patients reported improvements in tension, trouble sleeping, abnormal sweating, distress from hot flashes, satisfaction with hot-flash control, overall quality of life, and impact of hot flashes on quality of life. Patients also reported increases in appetite and dry mouth. Although data from a double-blind, placebo-controlled clinical trial would be necessary to more definitively elucidate the efficacy and toxicity of mirtazapine in patients with hot flashes, the available data suggest that mirtazapine is a reasonable treatment to consider in patients with hot flashes, particularly in those with anxiety and sleep disturbances.

Pilot evaluation of citalopram for the relief of hot flashes.

Symptoms associated with premature menopause are a significant problem for women with a history of breast cancer who cannot take hormone replacement therapy. Thus, effective nonhormonal alternatives are needed to manage hot flashes, the most prevalent symptom of menopause. Previous studies have defined that venlafaxine, an anti-depressant, is an effective treatment for such hot flashes. Based on suggestive anecdotal information, we set out to evaluate, in a pilot trial, whether the antidepressant citalopram might be a good nonhormonal treatment option to add to our armamentarium for controlling hot flashes. A prospective pilot study was developed in which patients were studied for 5 weeks, with the first week used to establish a baseline, followed by 4 weeks of treatment with citalopram. During the first week of treatment, 10 mg/day of citalopram was taken while 20 mg/day was taken during each of the following three weeks. Hot-flash diaries were completed daily, symptom diaries and quality-of-life items were completed weekly and the Profile of Mood States was completed at baseline and at week 5. Evaluable patients who completed the study had a mean hot-flash frequency reduction of 58% and a mean hot-flash score reduction of 64% from baseline to week 5. The patients finishing the study also reported decreased anger, tension and depression, as well as improved mood. This pilot trial suggests that citalopram may be an effective non-hormonal treatment for hot flashes in women who can tolerate it.

Pilot evaluation of gabapentin for treating hot flashes.

OBJECTIVE: To obtain pilot prospective data regarding the efficacy and tolerability of gabapentin for alleviating hot flashes. PATIENTS AND METHODS: This prospective single-arm clinical trial was conducted between July 26, 2001, and November 30, 2001. Patients underwent a baseline week and then 4 weeks of gabapentin treatment, with increasing doses during the first 3 weeks, from 300 to 600 to 900 mg/d. Data were obtained primarily from patient-completed questionnaires. RESULTS: Data from 20 evaluable women (of 24 entered in the trial) were available. Four patients discontinued use of gabapentin for perceived drug-related untoward symptoms, primarily related to light-headedness and dizziness. The 16 patients who completed this clinical trial had a mean reduction in hot flash frequency, in the fourth treatment week compared to the baseline week, of 66%. Their corresponding hot flash score (frequency times average severity) reduction was 70%. Additionally, patients who completed the 4 treatment weeks had a strong tendency to report an improvement in several other symptoms. CONCLUSION: Although a double-blind placebo-controlled clinical trial should be conducted to better elucidate the efficacy and toxicity of gabapentin in patients with hot flashes, the available data suggest that gabapentin is a reasonable treatment to consider in patients with hot flashes if they do not wish to use hormonal therapy.