Perioperative Opioid-sparing Strategies: Utility of Conventional NSAIDs in Adults.

Clin Ther. 2019 12;41(12):2612-2628

Authors: Martinez L, Ekman E, Nakhla N

Abstract
PURPOSE: Opioids have long been used to treat acute postsurgical and postprocedural pain; however, opioid-related adverse events (AEs) contribute to poor patient outcomes. In addition, perisurgical exposure to opioids can potentially increase the risk for opioid-use disorder. NSAIDs reduce pain and inflammation by a mechanism different from that of opioid analgesics and may be useful in reducing the need for opioid drugs as part of a multimodal analgesia strategy. We conducted this review to assess the effectiveness and tolerability of adjunctive conventional NSAIDs given systemically in the perioperative setting in terms of opioid-sparing effects observed postoperatively.
METHODS: Clinical trials published since 2000 that have assessed the opioid-sparing effects of conventional, nonselective NSAIDs were identified by a literature search using the PubMed search engine. Search terms were identified for the treatment of interest, the timing of the intervention, and the drugs of interest (NSAIDs). Data from studies that assessed opioid consumption outcomes with systemic NSAID administration were included in the review; data from studies in which NSAIDs were administered topically or via periarticular injection, local infiltration, or regional block were excluded.
FINDINGS: Upon full-text review of the search results, 32 studies were chosen for inclusion in this literature review. These studies included those that assessed diclofenac, ketorolac, ibuprofen, ketoprofen, dexketoprofen, flurbiprofen, lornoxicam, tenoxicam, meloxicam, and piroxicam. In studies in which NSAIDs were associated with opioid-sparing effects within the setting of patient-controlled analgesia, opioid use was reduced by 17%-∼50% with diclofenac, 9%-66% with ketorolac, 22%-46% with ibuprofen, 34%-66% with ketoprofen, 36%-50% with dexketoprofen, 38%-41% with tenoxicam, 36%-54% with lornoxicam, and ∼50% with flurbiprofen. No opioid-sparing effect was noted with meloxicam (1 study). The majority of studies that reported on pain-score changes revealed either pain reductions with NSAIDs versus placebo or similar pain scores between groups, indicating that NSAIDs did not compromise pain control. Although many studies found no difference in the prevalence of AEs in NSAID-treated patients compared with controls, several studies noted lower rates of nausea, vomiting, sedation, and pruritus with NSAIDs versus placebo. Conversely, NSAID-related AEs were few overall but included gastrointestinal bleeding, injection site reactions, transient oliguric renal failure, and dizziness. No surgery-related bleeding complications were observed.
IMPLICATIONS: NSAIDs have the potential to play an important role in reducing postoperative opioid requirements. Reducing the amount of opioids used could be expected to reduce opioid-related side effects and contribute to reversing the opioid epidemic.

PMID: 31733939 [PubMed - indexed for MEDLINE]

Immune Checkpoint Inhibitor Therapy: Key Principles When Educating Patients.

Clin J Oncol Nurs. 2019 06 01;23(3):271-280

Authors: Wood LS, Moldawer NP, Lewis C

Abstract
BACKGROUND: Immune checkpoint inhibitor (ICI) therapy is a fast-developing field within the spectrum of cancer care. ICIs are associated with distinctive immune-related adverse events (irAEs), reflecting their unique mechanisms of action.
OBJECTIVES: Effective management of irAEs requires early recognition and prompt reporting of their signs and symptoms; appropriate patient education is critical to maximizing this opportunity.
METHODS: A comprehensive literature search was conducted in the public domain concerning awareness, assessment, and management of irAEs associated with ICIs.
FINDINGS: Educational resources should provide timely, consistent, and personalized information, using a variety of teaching strategies that consider individual patient needs. Patient education should be developed with interprofessional team input and regularly reviewed in response to emerging guidance. Key messages include timing of therapeutic response and corresponding irAEs, early identification of irAEs, and the unique ability of ICIs to influence immune responses after treatment discontinuation.

PMID: 31099804 [PubMed - indexed for MEDLINE]

The Efficacy and Safety of Prochlorperazine in Patients With Acute Migraine: A Systematic Review and Meta-Analysis.

Headache. 2019 05;59(5):682-700

Authors: Golikhatir I, Cheraghmakani H, Bozorgi F, Jahanian F, Sazgar M, Montazer SH

Abstract
OBJECTIVE: The aim of this review was to evaluate the efficacy and safety of prochlorperazine (PCP) in patients with acute migraine headache in the emergency department (ED).
METHODS: Electronic databases (Medline, Scopus, Web of Science, and Cochrane) were searched for randomized clinical trials that investigated the effect of PCP on headache relief. The outcomes were the number of patients without headache or with reduced headache severity, the number of adverse events, and the need for rescue analgesia.
RESULTS: From 450 citations, 11 studies (n = 771) with 15 comparison arms met the inclusion criteria. Overall, PCP was more effective than placebo (OR = 7.23; 95% CI = 3.82-3.68), metoclopramide (OR = 2.89; 95% CI = 1.42-5.86), and other active comparators (OR = 3.70; 95% CI = 2.41-5.67) for headache relief. The odds ratio of experiencing adverse events with PCP compared with placebo was 5.79 (95% CI = 2.43-13.79). When PCP compared with other active comparators, no statistical difference was found regarding the overall number of adverse events (OR = 1.88; 95% CI = 0.99-3.59). However, PCP significantly increased the odds of akathisia/dystonia (OR = 2.55; 95% CI = 1.03-6.31). The request for rescue analgesia was significantly lower in the PCP group compared with other groups (16% vs 84%; OR = 0.16; 95% CI = 0.09-27).
CONCLUSIONS: For adult patients with acute migraine, PCP could effectively abort the acute attack and reduce the request for rescue analgesia in the ED. However, compared with placebo, PCP could increase the risk of adverse events.

PMID: 30990883 [PubMed - indexed for MEDLINE]

Efficacy and safety of ombitasvir/paritaprevir/ritonavir and dasabuvir with low-dose ribavirin in patients with chronic hepatitis C virus genotype 1a infection without cirrhosis.

J Viral Hepat. 2019 08;26(8):1027-1030

Authors: Poordad F, Sedghi S, Pockros PJ, Ravendhran N, Reindollar R, Lucey MR, Epstein M, Bank L, Bernstein D, Trinh R, Krishnan P, Polepally AR, Unnebrink K, Martinez M, Nelson DR

Abstract
Patients infected with hepatitis C virus (HCV) treated with interferon-free direct-acting antivirals may still require ribavirin. However, ribavirin is associated with adverse events that can limit its use. This open-label, multicentre, Phase 3 study evaluated the safety and efficacy of ombitasvir/paritaprevir/ritonavir + dasabuvir (OBV/PTV/r + DSV) with low-dose ribavirin for 12 weeks in genotype 1a-infected patients without cirrhosis. The primary efficacy endpoint was sustained virologic response at post-treatment Week 12 (SVR12). The primary safety endpoint was haemoglobin <10 g/dL during treatment and decreased from baseline. Overall, 105 patients enrolled. The SVR12 rate was 89.5% (n/N = 94/105; 95% CI, 83.7-95.4). The study did not achieve noninferiority versus the historic SVR12 rate for OBV/PTV/r + DSV plus weight-based ribavirin. Five patients experienced virologic failure, four discontinued, and two had missing SVR12 data. Excluding nonvirologic failures, the SVR12 rate was 94.9% (n/N = 94/99). One patient met the primary safety endpoint. OBV/PTV/r + DSV plus low-dose ribavirin offers an alternative option for patients in whom full-dose ribavirin may compromise tolerability, although noninferiority to the weight-based ribavirin regimen was not met.

PMID: 30980576 [PubMed - indexed for MEDLINE]

Dynamic features of cardiac vector as alternative markers of drug-induced spatial dispersion.

J Pharmacol Toxicol Methods. 2020 Jul 06;:106894

Authors: Cruces PD, Torkar D, Arini PD

Abstract
INTRODUCTION: The abnormal amplification of ventricular repolarization dispersion (VRD) has long been linked to proarrhythmia risk. Recently, the measure of VRD through electrocardiogram intervals has been strongly questioned. The search for an efficient and non-invasive surrogate marker of drug-induced dispersion effects constitute an urgent research challenge.
METHODS: Herein, drug-induced ventricular dispersion is generated by d-Sotalol supply in an In-vitro rabbit heart model. A cilindrical chamber simulates the thorax and a multi-electrode net is used to obtain spatial electrocardiographic signals. Cardiac vector dynamics is captured by novel velocity cardiomarkers obtained by quaternion methods. Through statistical analysis and machine learning technics, we compute potential dispersion markers that could define proarrhythmic risk.
RESULTS: The cardiomarkers with the greatest statistical significance, both obtained from the electrical cardiac vector, were: the QTω, which is the difference between first and last maxima of angular velocity and λ21vT, the roundness of linear velocity. When comparing with the performance of the current standards (89%), this pair was able to correctly separate 21 out of 22 experiments achieving a performance of 95%. Moreover, the QTω computes in a much more robust basis the QT interval, the current index for drug regulation.
DISCUSSION: These velocity markers circumvent the problems of accuratelly finding the fiducial points such as the always tricky T-wave end. Given the high performance they achieved, it is provided a promising outcome for future applications to the detection of anomalous changes of heterogeneity that may be useful for the purposes of torsadogenic toxicity studies.

PMID: 32645483 [PubMed - as supplied by publisher]

A phase II, open-label, extension study of long-term patisiran treatment in patients with hereditary transthyretin-mediated (hATTR) amyloidosis.

Orphanet J Rare Dis. 2020 Jul 08;15(1):179

Authors: Coelho T, Adams D, Conceição I, Waddington-Cruz M, Schmidt HH, Buades J, Campistol J, Berk JL, Polydefkis M, Wang JJ, Chen J, Sweetser MT, Gollob J, Suhr OB

Abstract
BACKGROUND: Patisiran, an RNA interference therapeutic, has demonstrated robust reduction of wild-type and mutant transthyretin protein and was able to improve polyneuropathy and quality of life following 18 months of treatment in patients with hereditary transthyretin-mediated (hATTR) amyloidosis. In this 24-month Phase II open-label extension study, we evaluated the effects of patisiran treatment (0.3 mg/kg intravenously every 3 weeks) on safety, serum transthyretin levels, and clinical parameters. Efficacy assessments included modified Neuropathy Impairment Score +7 (mNIS+7) and multiple disease-relevant measures. Cardiac assessments were performed in a pre-specified cardiac subgroup.
RESULTS: Twenty-seven patients entered this study, including 12 (44%) with ambulation difficulties due to their neuropathy and 11 (41%) who met criteria for the cardiac subgroup. During treatment, the majority of adverse events were mild/moderate in severity; there were no drug-related adverse events leading to treatment discontinuation. The most common drug-related adverse events were flushing and infusion-related reactions (22% each). Patisiran resulted in rapid, robust (~ 82%), and sustained reduction of mean transthyretin levels over 24 months. A mean 6.95-point decrease (improvement) in mNIS+7 from baseline was observed at 24 months. Patisiran's impact on mNIS+7 was irrespective of concomitant tafamidis or diflunisal use, sex, or age. Clinical assessments of motor function, autonomic symptoms, disease stage, and quality of life remained stable over 24 months. No significant changes were observed for echocardiographic measures or cardiac biomarkers in the cardiac subgroup. Exploratory analyses demonstrated improvements in nerve-fiber density with corresponding reductions in amyloid burden observed in skin biopsies over 24 months.
CONCLUSIONS: Long-term treatment with patisiran had an acceptable safety profile and was associated with halting/improvement of polyneuropathy progression in patients with hATTR amyloidosis.
TRIAL REGISTRATION: The study was registered at ClinicalTrials.gov (identifier: NCT01961921 ) on October 14, 2013.

PMID: 32641071 [PubMed - in process]

Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study.

Lancet Oncol. 2020 05;21(5):671-684

Authors: Abou-Alfa GK, Sahai V, Hollebecque A, Vaccaro G, Melisi D, Al-Rajabi R, Paulson AS, Borad MJ, Gallinson D, Murphy AG, Oh DY, Dotan E, Catenacci DV, Van Cutsem E, Ji T, Lihou CF, Zhen H, Féliz L, Vogel A

Abstract
BACKGROUND: Fibroblast growth factor receptor (FGFR) 2 gene alterations are involved in the pathogenesis of cholangiocarcinoma. Pemigatinib is a selective, potent, oral inhibitor of FGFR1, 2, and 3. This study evaluated the safety and antitumour activity of pemigatinib in patients with previously treated, locally advanced or metastatic cholangiocarcinoma with and without FGFR2 fusions or rearrangements.
METHODS: In this multicentre, open-label, single-arm, multicohort, phase 2 study (FIGHT-202), patients aged 18 years or older with disease progression following at least one previous treatment and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 recruited from 146 academic or community-based sites in the USA, Europe, the Middle East, and Asia were assigned to one of three cohorts: patients with FGFR2 fusions or rearrangements, patients with other FGF/FGFR alterations, or patients with no FGF/FGFR alterations. All enrolled patients received a starting dose of 13·5 mg oral pemigatinib once daily (21-day cycle; 2 weeks on, 1 week off) until disease progression, unacceptable toxicity, withdrawal of consent, or physician decision. The primary endpoint was the proportion of patients who achieved an objective response among those with FGFR2 fusions or rearrangements, assessed centrally in all patients who received at least one dose of pemigatinib. This study is registered with ClinicalTrials.gov, NCT02924376, and enrolment is completed.
FINDINGS: Between Jan 17, 2017, and March 22, 2019, 146 patients were enrolled: 107 with FGFR2 fusions or rearrangements, 20 with other FGF/FGFR alterations, 18 with no FGF/FGFR alterations, and one with an undetermined FGF/FGFR alteration. The median follow-up was 17·8 months (IQR 11·6-21·3). 38 (35·5% [95% CI 26·5-45·4]) patients with FGFR2 fusions or rearrangements achieved an objective response (three complete responses and 35 partial responses). Overall, hyperphosphataemia was the most common all-grade adverse event irrespective of cause (88 [60%] of 146 patients). 93 (64%) patients had a grade 3 or worse adverse event (irrespective of cause); the most frequent were hypophosphataemia (18 [12%]), arthralgia (nine [6%]), stomatitis (eight [5%]), hyponatraemia (eight [5%]), abdominal pain (seven [5%]), and fatigue (seven [5%]). 65 (45%) patients had serious adverse events; the most frequent were abdominal pain (seven [5%]), pyrexia (seven [5%]), cholangitis (five [3%]), and pleural effusion (five [3%]). Overall, 71 (49%) patients died during the study, most frequently because of disease progression (61 [42%]); no deaths were deemed to be treatment related.
INTERPRETATION: These data support the therapeutic potential of pemigatinib in previously treated patients with cholangiocarcinoma who have FGFR2 fusions or rearrangements.
FUNDING: Incyte Corporation.

PMID: 32203698 [PubMed - indexed for MEDLINE]

Do drugs used in obstetric anesthesia interfere with early breastfeeding? What determines drug safety in lactation? Part 1.

Dev Period Med. 2019;23(4):227-232

Authors: Wilińska M, Walas W, Kamińska E, Malec Milewska M, Sękowska A, Helwich E

Abstract
The issues concerning the transfer of drugs into mothers' milk and their influence on breastfed babies have not been fully studied. Assessment of the situation should include such aspects as drug transfer into fetal blood and into mother's milk, the real risk of inhibiting lactogenesis 2 in women after birth, as well as the psychological consequences for the mother of suspending breastfeeding. The risk of feeding a newborn with formula based on cow's milk is another fateful issue. The following paper presents the pharmacokinetic characteristics of drugs which determine their transfer level through the placenta and into mother's milk during the perinatal period and lactation.

PMID: 31913138 [PubMed - indexed for MEDLINE]

Critical Care Management of Toxicities Associated With Targeted Agents and Immunotherapies for Cancer.

Crit Care Med. 2020 01;48(1):10-21

Authors: Gutierrez C, McEvoy C, Munshi L, Stephens RS, Detsky ME, Nates JL, Pastores SM

Abstract
OBJECTIVES: To describe the most common serious adverse effects and organ toxicities associated with emerging therapies for cancer that may necessitate admission to the ICU.
DATA SOURCES AND STUDY SELECTION: PubMed and Medline search of relevant articles in English on the management of adverse effects of immunotherapy for cancer.
DATA EXTRACTION AND DATA SYNTHESIS: Targeted therapies including tyrosine kinase inhibitors, monoclonal antibodies, checkpoint inhibitors, and immune effector cell therapy have improved the outcome and quality of life of patients with cancer. However, severe and life-threatening side effects can occur. These toxicities include infusion or hypersensitivity reactions, cytokine release syndrome, pulmonary, cardiac, renal, hepatic, and neurologic toxicities, hemophagocytic lymphohistiocytosis, opportunistic infections, and endocrinopathies. Cytokine release syndrome is the most common serious toxicity after administration of monoclonal antibodies and immune effector cell therapies. Most of the adverse events from immunotherapy results from an exaggerated T-cell response directed against normal tissue, resulting in the generation of high levels of proinflammatory cytokines. Toxicities from targeted therapies are usually secondary to "on target toxicities." Management is largely supportive and may include discontinuation of the specific agent, corticosteroids, and other immune suppressing agents for severe (grade 3 or 4) immune-related adverse events like neurotoxicity and pneumonitis.
CONCLUSIONS: The complexity of toxicities associated with modern targeted and immunotherapeutic agents for cancer require a multidisciplinary approach among ICU staff, oncologists, and organ specialists and adoption of standardized treatment protocols to ensure the best possible patient outcomes.

PMID: 31725440 [PubMed - indexed for MEDLINE]

Exercise-induced attenuation of treatment side-effects in patients with newly diagnosed prostate cancer beginning androgen-deprivation therapy: a randomised controlled trial.

BJU Int. 2020 01;125(1):28-37

Authors: Ndjavera W, Orange ST, O'Doherty AF, Leicht AS, Rochester M, Mills R, Saxton JM

Abstract
OBJECTIVES: (i) To assess whether exercise training attenuates the adverse effects of treatment in patients with newly diagnosed prostate cancer beginning androgen-deprivation therapy (ADT), and (ii) to examine whether exercise-induced improvements are sustained after the withdrawal of supervised exercise.
PATIENTS AND METHODS: In all, 50 patients with prostate cancer scheduled for ADT were randomised to an exercise group (n = 24) or a control group (n = 26). The exercise group completed 3 months of supervised aerobic and resistance exercise training (twice a week for 60 min), followed by 3 months of self-directed exercise. Outcomes were assessed at baseline, 3- and 6-months. The primary outcome was difference in fat mass at 3-months. Secondary outcomes included: fat-free mass, cardiopulmonary exercise testing variables, QRISK® 2 (ClinRisk Ltd, Leeds, UK) score, anthropometry, blood-borne biomarkers, fatigue, and quality of life (QoL).
RESULTS: At 3-months, exercise training prevented adverse changes in peak O2 uptake (1.9 mL/kg/min, P = 0.038), ventilatory threshold (1.7 mL/kg/min, P = 0.013), O2 uptake efficiency slope (0.21, P = 0.005), and fatigue (between-group difference in Functional Assessment of Chronic Illness Therapy-Fatigue score of 4.5 points, P = 0.024) compared with controls. After the supervised exercise was withdrawn, the differences in cardiopulmonary fitness and fatigue were not sustained, but the exercise group showed significantly better QoL (Functional Assessment of Cancer Therapy-Prostate difference of 8.5 points, P = 0.034) and a reduced QRISK2 score (-2.9%, P = 0.041) compared to controls.
CONCLUSION: A short-term programme of supervised exercise in patients with prostate cancer beginning ADT results in sustained improvements in QoL and cardiovascular events risk profile.

PMID: 31605663 [PubMed - indexed for MEDLINE]

A Phase I/II Open-Label Study of Nivolumab in Previously Treated Advanced or Recurrent Nasopharyngeal Carcinoma and Other Solid Tumors.

Oncologist. 2019 07;24(7):891-e431

Authors: Ma Y, Fang W, Zhang Y, Yang Y, Hong S, Zhao Y, Tendolkar A, Chen L, Xu D, Sheng J, Zhao H, Zhang L

Abstract
LESSONS LEARNED: Nivolumab treatment at doses of 3 mg/kg once every 2 weeks (Q2W), 240 mg Q2W, and 360 mg once every 3 weeks was well tolerated in the Chinese population, with no new safety signals identified.Comparison of intensive pharmacokinetic profiles of nivolumab at 3 mg/kg Q2W in Chinese versus global populations revealed no ethnic differences of nivolumab treatment.Nivolumab shows promising preliminary antitumor activity in nasopharyngeal carcinoma.
BACKGROUND: This phase I/II study investigated the safety and pharmacokinetics (PK) of nivolumab (anti-programmed cell death-1 monoclonal antibody) in Chinese patients with nasopharyngeal carcinoma (NPC) and other solid tumors.
METHODS: A dose evaluation phase (3 mg/kg once every 2 weeks [Q2W]) was followed by a cohort expansion phase (3 mg/kg Q2W or flat doses of 240 mg Q2W or 360 mg once every 3 weeks).
RESULTS: In the dose evaluation phase, 8/8 patients completed one cycle with no dose-limiting toxicities. At data cutoff, 46/51 patients were evaluable for safety (all cohorts). Treatment-related adverse events (TRAEs) occurred in 35 (76%) patients and were primarily grade 1-2; one patient (3 mg/kg Q2W) discontinued because of study drug toxicity. Intensive PK profiles at 3 mg/kg, 240 mg, and 360 mg were well characterized at single and multiple doses of nivolumab. An objective response was determined in six (6/46) patients, four (4/32) of whom had NPC tumors.
CONCLUSION: Nivolumab monotherapy at 3 mg/kg and flat doses of 240 mg and 360 mg were well tolerated in this Chinese patient population, with PK profiles at 3 mg/kg being similar to those of global patients. Preliminary efficacy results showed promising antitumor activity of nivolumab in advanced NPC.

PMID: 31048330 [PubMed - indexed for MEDLINE]

Adverse Event Management in Patients with BRAF V600E-Mutant Non-Small Cell Lung Cancer Treated with Dabrafenib plus Trametinib.

Oncologist. 2019 07;24(7):963-972

Authors: Chalmers A, Cannon L, Akerley W

Abstract
Therapies for advanced non-small cell lung cancer (NSCLC) continue to become more sophisticated. Chemotherapeutics are giving way to newer approaches such as immune checkpoint inhibitors and targeted therapies for greater efficacy and improved outcomes. Dabrafenib plus trametinib combination therapy was first approved for the treatment of metastatic melanoma harboring the BRAF V600-mutation in 2014. In 2017, the U.S. Food and Drug Administration approved the combination for patients with NSCLC with the same mutation based on an ≈ 65% response rate and median progression-free survival of 10-11 months. BRAF mutations are a high-frequency event in melanoma (≈ 50%), whereas the overall incidence in lung cancer is ≈ 2%, but similar in number, because of the high incidence of the disease. As a new approach in NSCLC treatment, dabrafenib plus trametinib has a unique toxicity profile that is likely unfamiliar to care providers in thoracic and general oncology who have not used the combination to treat patients with melanoma. Common adverse events such as pyrexia, fatigue, and nausea, as well as a range of less frequent cutaneous, ocular, and hemorrhagic events, can be observed during treatment with dabrafenib plus trametinib. Previous experience in metastatic melanoma revealed that these events can be effectively managed to improve patient quality of life and reduce unnecessary drug discontinuation. The aim of this review is to summarize treatment guidelines, along with key insights obtained from previous clinical-trial and real-world experience in patients with metastatic melanoma, to properly manage toxicities associated with dabrafenib plus trametinib for NSCLC. IMPLICATIONS FOR PRACTICE: The combination of dabrafenib plus trametinib has demonstrated substantial clinical activity in patients with BRAF V600E-mutant non-small cell lung cancer, leading to U.S. Food and Drug Administration approval. Although the combination has a manageable safety profile, many toxicities associated with the regimen may not be familiar to thoracic specialists or general oncologists. Extensive clinical experience with the combination in patients with metastatic melanoma has provided a wealth of strategies to identify and manage adverse events associated with dabrafenib plus trametinib. These can be used by medical oncologists to enhance early recognition of toxicities and facilitate effective management, thereby improving quality of treatment for patients.

PMID: 30598499 [PubMed - indexed for MEDLINE]

Outcomes and Toxicities of Programmed Death-1 (PD-1) Inhibitors in Hodgkin Lymphoma Patients in the United States: A Real-World, Multicenter Retrospective Analysis.

Oncologist. 2019 07;24(7):955-962

Authors: Bair SM, Strelec LE, Feldman TA, Ahmed G, Armand P, Shah NN, Singavi AN, Reddy N, Khan N, Andreadis C, Vu K, Huntington SF, Giri S, Ujjani C, Howlett C, Faheem M, Youngman MR, Nasta SD, Landsburg DJ, Schuster SJ, Svoboda J

Abstract
BACKGROUND: Although classical Hodgkin lymphoma (cHL) is highly curable, 20%-30% of patients will not be cured with conventional treatments. The programmed death-1 (PD-1) inhibitors (PD-1i) nivolumab and pembrolizumab have been Food and Drug Administration-approved for relapsed/refractory (R/R) cHL. There is limited data on the real-world experience with PD-1i in cHL and it is unknown whether fewer selected patients treated with PD-1i derive benefits similar to those observed in published trials.
MATERIALS AND METHODS: We performed a multicenter, retrospective analysis of R/R cHL patients treated with PD-1i in the nontrial setting. The primary objective was to describe progression-free survival (PFS) and overall survival (OS) in this population. Secondary objectives were to characterize response rates, toxicities, discontinuation patterns, and post-PD-1i therapies.
RESULTS: The study included 53 patients from nine U.S. centers. Overall response rate (ORR), complete response (CR), and partial response (PR) to PD-1i were 68%, 45%, and 23%, respectively. Twelve-month OS and PFS were 89% and 75%, respectively; median PFS was 29 months. Ninety-six percent of patients with CR continue to respond at a median follow-up of 20 months. Toxicities were similar to those previously described. Seventy percent of patients treated with systemic therapy after PD-1i demonstrated objective responses.
CONCLUSION: To our knowledge, this analysis is the first describing real-world experience with PD-1i in cHL patients in the U.S. Here, we demonstrate similar response rates compared to prior studies. The toxicity profile of PD-1i was similar to that seen in previous studies; we further describe toxicity patterns in those with prior autoimmune disease or allogeneic transplant. Post-PD-1i systemic therapies appear active. These results support the effectiveness and tolerability of PD-1i therapy in R/R cHL in a real-world setting.
IMPLICATIONS FOR PRACTICE: Two PD-1 inhibitors have recently been approved for patients with relapsed/refractory classical Hodgkin lymphoma based on results from nonrandomized clinical trials. However, to date, there have been no studies evaluating the effectiveness and toxicity profile of these drugs in the real-world setting in the U.S. The present study demonstrates that patients treated in a real-world context experience similar rates of overall effectiveness compared with published clinical trials. Patients who discontinue PD-1 inhibitors may experience clinical responses to subsequent treatment with systemic chemotherapy or targeted therapy. This study provides clinicians with further insight into the effectiveness and tolerability of PD-1 inhibitors and suggests that when patients progress while on these drugs, conventional systemic chemotherapy may be an effective treatment option.

PMID: 30568021 [PubMed - indexed for MEDLINE]

The Influence of Side Effect Information Framing on Nocebo Effects.

Ann Behav Med. 2019 06 04;53(7):621-629

Authors: Faasse K, Huynh A, Pearson S, Geers AL, Helfer SG, Colagiuri B

Abstract
BACKGROUND: One contributing factor to the development of nocebo effects is information provided about possible side effects. However, nondisclosure of information can be problematic.
PURPOSE: We assessed whether positively framed side effect information (highlighting likelihood of not experiencing side effects) can reduce nocebo effects compared to negatively framed information (highlighting likelihood of experiencing side effects).
METHODS: One hundred twelve participants took part in research ostensibly assessing the influence of benzodiazepines (actually sham capsules) on anxiety. Participants were randomized to receive a sham capsule with positively or negatively framed information about four side effects, or a no-treatment control condition. Side effect expectations were assessed after information provision. Framed side effects and other unmentioned symptoms were assessed during the session and 24-hr follow-up.
RESULTS: Nocebo effects occurred in symptoms presented as side effects (regardless of framing) during the study session and follow-up (ps < .003). At follow-up, there was also a nocebo effect in other unmentioned symptoms (p = .018). Positive framing reduced side effect symptoms compared with negative framing during the study session (p = .037), but this effect was no longer present at follow-up (p = .53). Side effect expectations did not differ between the framing conditions (p = .14).
CONCLUSIONS: Positive framing reduced side effects short-term, but not at follow-up. Expectations did not differ between negative and positive framing. Nocebo effects appeared to generalize to other unmentioned symptoms over a 24-hr period. Further research is needed to determine whether the initial impact of positive framing can be maintained over time.

PMID: 30204841 [PubMed - indexed for MEDLINE]

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A retrospective case-controlled cohort study of inpatient drug induced liver injury: the RIDDLE study.

Transl Gastroenterol Hepatol. 2020;5:33

Authors: Worland T, Chin KL, Rodrigues B, Nicoll A

Abstract
Background: Identification of risk factors for drug-induced liver injury (DILI) has been hindered by the unpredictable incidence and idiosyncratic nature of DILI. The aim of this study was to identify characteristic host risk factors for DILI.
Methods: A retrospective cohort study was performed examining all patients admitted with a diagnosis of DILI over a 5.5-year period. Cases were compared to a control group non-exposed to DILI using propensity score-derived inverse probability weights. Patients with DILI due to alcohol or paracetamol were excluded from analysis.
Results: Seventy-two cases of DILI admitted to hospital were identified. Antimicrobials caused 56.9% of cases, with amoxicillin-clavulanate the single most common agent, responsible for 13.9% of cases. DILI cohort median age (50.2±36 years) was significantly younger than controls (65.0±38 years) (P<0.001). Pre-existing chronic liver disease (OR, 3.44; 95% CI, 1.38-8.59; P=0.008), length of stay (P<0.001) and in-hospital death (P=0.009) were more likely to be associated with DILI cases. There was no correlation with sex (OR male, 0.92; 95% CI, 0.50-1.67; P=0.78), presence of comorbid autoimmune disease (OR, 1.44; 95% CI, 0.68-3.05; P=0.35), past drug allergies (OR, 1.71; 95% CI, 0.92-3.16; P=0.09), or atopy (OR, 0.87; 95% CI, 0.42-1.82; P=0.72).
Conclusions: Younger age and presence of chronic liver disease were associated with an admission with DILI; however, it remains difficult to predict the population at risk of DILI on clinical grounds and putative risk factors such as female gender, and history of other drug allergies and autoimmunity, were not demonstrated in this study.

PMID: 32632384 [PubMed]

Mycophenolate sodium in the treatment of corticosteroid-refractory non-infectious inflammatory uveitis (MySTRI study).

Eye (Lond). 2020 Jul 06;:

Authors: Chen TS, Tsang WM, Enkh-Amgalan I, Hwang YS

Abstract
OBJECTIVES: To evaluate the therapeutic effect and safety profile of next generation mycophenolate sodium (MPS), which is different from mycophenolate mofetil with an enteric-coated formulation, in corticosteroid-refractory non-infectious inflammatory uveitis (CRU) patients.
METHODS: Prospective, uncontrolled, open-label interventional case series. Forty consecutive patients at a tertiary uveitis referral centre received 6 months of oral MPS as the treatment regimen with follow-up 12 months. The main outcome measures were best-corrected visual acuity (BCVA), inflammatory index, steroid-sparing effect of tapering prednisone to ≤10 mg daily and side effects.
RESULTS: Mean age of enroled patients was 49 (49 ± 13) years and 29 (72.5%) were female. Thirty-six (90.0%) had bilateral disease. There were 0 (0%) anterior uveitis, 2 (5.0%) intermediate uveitis, 22 (55.0%) posterior uveitis, and 16 (40.0%) panuveitis. Vogt-Koyanagi-Harada disease was the most common diagnosis (17/40, 42.5%), followed by idiopathic panuveitis (8/40, 20%) and idiopathic retinal vasculitis (5/40, 12.5%). LogMAR BCVA improved from 0.9 (SD = 0.09) to 0.31 (SD = 0.08) after 6 months of MPS with good steroid-sparing effect (p = 0.012). Further maintenance in LogMAR BCVA was evident after MPS discontinuation from 6th month to 12th month, from 0.31 (SD = 0.08) to 0.33 (SD = 0.07), respectively (p = 0.81). MPS was the only immunosuppressive drug needed to reach quiescent state in 29 patients (72.5%). The drug-related safety profile was satisfactory.
CONCLUSION: MPS is an effective steroid-sparing drug for the treatment of CRU. The effect seen was not only during the 6 months of therapy, but also extended to 12 months to maintain BCVA and inflammation control. The side effects were acceptable.

PMID: 32632297 [PubMed - as supplied by publisher]

Primary chemoablation of low-grade upper tract urothelial carcinoma using UGN-101, a mitomycin-containing reverse thermal gel (OLYMPUS): an open-label, single-arm, phase 3 trial.

Lancet Oncol. 2020 Jun;21(6):776-785

Authors: Kleinmann N, Matin SF, Pierorazio PM, Gore JL, Shabsigh A, Hu B, Chamie K, Godoy G, Hubosky S, Rivera M, O'Donnell M, Quek M, Raman JD, Knoedler JJ, Scherr D, Stern J, Weight C, Weizer A, Woods M, Kaimakliotis H, Smith AB, Linehan J, Coleman J, Humphreys MR, Pak R, Lifshitz D, Verni M, Adibi M, Amin MB, Seltzer E, Klein I, Konorty M, Strauss-Ayali D, Hakim G, Schoenberg M, Lerner SP

Abstract
BACKGROUND: Most patients with low-grade upper tract urothelial cancer are treated by radical nephroureterectomy. We aimed to assess the safety and activity of a non-surgical treatment using instillation of UGN-101, a mitomycin-containing reverse thermal gel.
METHODS: In this open-label, single-arm, phase 3 trial, participants were recruited from 24 academic sites in the USA and Israel. Patients (aged ≥18 years) with primary or recurrent biopsy-proven, low-grade upper tract urothelial cancer (measuring 5-15 mm in maximum diameter) and an Eastern Cooperative Oncology Group performance status score of less than 3 (Karnofsky Performance Status score >40) were registered to receive six instillations of once-weekly UGN-101 (mitomycin 4 mg per mL; dosed according to volume of patient's renal pelvis and calyces, maximum 60 mg per instillation) via retrograde catheter to the renal pelvis and calyces. All patients had a planned primary disease evaluation 4-6 weeks after the completion of initial therapy, in which the primary outcome of complete response was assessed, defined as negative 3-month ureteroscopic evaluation, negative cytology, and negative for-cause biopsy. Activity (complete response, expected to occur in >15% of patients) and safety were assessed by the investigator in all patients who received at least one dose of UGN-101. Data presented are from the data cutoff on May 22, 2019. This study is registered with ClinicalTrials.gov, NCT02793128.
FINDINGS: Between April 6, 2017, and Nov 26, 2018, 71 (96%) of 74 enrolled patients received at least one dose of UGN-101. 42 (59%, 95% CI 47-71; p<0·0001) patients had a complete response at the primary disease evaluation visit. The median follow-up for patients with a complete response was 11·0 months (IQR 5·1-12·4). The most frequently reported all-cause adverse events were ureteric stenosis in 31 (44%) of 71 patients, urinary tract infection in 23 (32%), haematuria in 22 (31%), flank pain in 21 (30%), and nausea in 17 (24%). 19 (27%) of 71 patients had study drug-related or procedure-related serious adverse events. No deaths were regarded as related to treatment.
INTERPRETATION: Primary chemoablation of low-grade upper tract urothelial cancer with intracavitary UGN-101 results in clinically significant disease eradication and might offer a kidney-sparing treatment alternative for these patients.
FUNDING: UroGen Pharma.

PMID: 32631491 [PubMed - in process]

Content and impact of pharmacy services for patients with Parkinson's disease: A systematic review and meta-analysis.

Medicine (Baltimore). 2020 Jul 02;99(27):e20758

Authors: Yi ZM, Li TT, Tang QY, Zhang Y, Willis S, Zhai SD

Abstract
BACKGROUND: Medicines optimisation is important for the management of Parkinson's disease (PD). As many patients with PD have other long-term conditions, treatment is complex and risk of adverse events for these patients is high.
OBJECTIVE: To explore the role of pharmacists and impact of pharmacy interventions for PD patients.
METHODS: We comprehensively searched PubMed, Embase, the Cochrane Library and Chinese databases Sinomed, China National Knowledge Infrastructure to identify studies reporting pharmacist interventions and pharmacy services for PD patients using a predefined search strategy. The search period was from inception to March 2019. We also manually searched the reference list of included studies and ClinicalTrials.gov. We conducted meta-analyses to synthesize the evidence quantitatively.
RESULTS: A total of 1607 studies were identified by applying the search criteria. After screening, 19 cross-sectional and case-controlled studies with 1458 PD patients from 9 countries were included. Pharmacist interventions for PD patients most commonly related to adverse drug reactions (ADRs) (13 studies), adherence assessment (12 studies), medication review (12 studies), identification of drug interactions (11 studies), monitoring response to medication therapy (11 studies), identification of inappropriate medication (11 studies), and patient education (10 studies). Most pharmacy services were provided in outpatient settings (13 studies). Reported impact measures included adherence (8 studies), quality of life (7 studies), and identification of drug-related problems (6 studies) such as ADRs (393 times out of 1760 times, 22.33%, 6 studies), inappropriate drug choice (349 times, 19.83%, 6 studies), inappropriate dosage (335 times, 19.03%, 6 studies), inappropriate drug use (257 times, 14.60%, 3 studies) and drug-drug interactions (146 times, 8.3%, 4 studies). Pooled results from 3 studies indicated no statistically significant impact of pharmacy services on all subscales of PD Questionnaire-39.
CONCLUSION: ADRs were the most widely reported drug-related problems for PD patients; pharmacy services may have a role to play in medication adherence but were not found to impact on quality of life.

PMID: 32629653 [PubMed - in process]

Hospital contacts due to hepatobiliary adverse events in >5000 patients with inflammatory joint disease treated with originator or biosimilar etanercept (SB4): an observational nationwide study applying linkage between DANBIO and national registries.

Ann Rheum Dis. 2020 06;79(6):846-848

Authors: Glintborg B, Georgiadis S, Loft AG, Linauskas A, Lindegaard H, Hendricks O, Jensen DV, Andersen BL, Danebod K, Villumsen A, Eng G, Wiell C, Manilo N, Kristensen S, Raun J, Grydehøj J, Chrysidis S, Nørgaard M, Mehnert F, Krogh NS, Hetland ML

PMID: 32111583 [PubMed - indexed for MEDLINE]