Use of colony-stimulating factor primary prophylaxis and incidence of febrile neutropenia from 2010 to 2016: a longitudinal assessment

Background: Guidelines recommend primary prophylactic use of colony-stimulating factor (PP-CSF) when risk of febrile neutropenia (FN) – based on chemotherapy and patient risk factors – is high. Whether and how PP-CSF use may have changed over time (e.g. due to guideline revisions, increasing use of myelosuppressive regimens, controversy regarding inappropriate CSF use), and whether there has been a concomitant change in the incidence of FN, is unknown.

Methods: A retrospective cohort design and data from two US healthcare claims repositories were employed. The study population included patients who had non-metastatic cancer of the breast, colon/rectum, lung or ovaries, or non-Hodgkin’s lymphoma (NHL), and who received myelosuppressive chemotherapy regimens with an intermediate/high risk for FN. For each patient, the first cycle of the first course was characterized in terms of PP-CSF use and FN episodes. Crude incidence proportions for PP-CSF and FN during the first cycle were estimated by calendar quarter (2010–2016); multivariable logistic regression models were used to estimate quarter-specific adjusted mean probabilities of FN by PP-CSF use.

Results: The study population totaled 142,730 patients with breast cancer (61%), colorectal cancer (14%), NHL (11%), ovarian cancer (10%) or lung cancer (5%). PP-CSF use increased from 52% in 1Q2010 to 58% in 4Q2016; pegfilgrastim was the most commonly used agent (>96% across quarters). PP-CSF administration on the same day as chemotherapy ranged from 8 to 11% until 1Q2015, and increased to 64% by 4Q2016. Adjusted incidence proportions for FN in the first chemotherapy cycle ranged from 2.7% (95% CI: 2.3–3.0) to 3.7% (95% CI: 3.1–4.3) among those who did not receive PP-CSF, and was 2.6% (95% CI: 2.5–2.7) across quarters among those who received PP-CSF.

Conclusions: Although the use of PP-CSF is commonplace in current US clinical practice, underutilization in cancer patients receiving chemotherapy regimens with an intermediate/high risk for FN may still be an issue. Use of same-day PP-CSF increased markedly from the end of 2015, although this finding reflects (at least in part) increased uptake of pegfilgrastim delivered via an on-body injector as well as the recent change in clinical practice guidelines. Overall, patients receiving PP-CSF appear to have a lower risk of FN during the first cycle of chemotherapy.     

Cardiovascular events associated with nicorandil administration prior to primary percutaneous coronary intervention in patients with acute ST-segment elevated myocardial infarction: a systematic review and meta-analysis

Introduction: Nicorandil may exert cardioprotective effects in ischemic heart disease. However, its efficacy in combination with early reperfusion is uncertain. The authors performed a meta-analysis of the short- and long-term clinical outcomes of nicorandil administration at the time of primary percutaneous coronary intervention (PCI) in patients with ST-elevated myocardial infarction (STEMI).

Methods: PubMed, MEDLINE, Embase, and the Cochrane Library databases were systematically searched for eligible randomized controlled studies. The primary endpoint was major adverse cardiovascular events (MACE), both in-hospital and post-discharge. The secondary endpoint was the incidence of no-reflow phenomenon.

Results: Ten studies were included (n = 1105). Mean patient age was 63.0 ± 10.0 years; 76.6% of patients were male. Compared with controls who received primary PCI, combined nicorandil/primary PCI significantly reduced in-hospital MACE (pooled odds ratio [OR] 0.16; 95% confidence interval [CI] 0.09–0.27), follow-up MACE (pooled OR 0.53; 95% CI 0.37–0.75), and total MACE (pooled OR 0.27; 95% CI 0.15–0.49). The combined treatment also reduced the incidence of no-reflow phenomenon (pooled OR 0.34; 95% CI 0.23–0.50).

Conclusion: Nicorandil administration at the time of primary PCI is associated with reduced MACE (both short- and long-term) and no-reflow phenomenon in patients with STEMI.     

Efficacy of istradefylline for gait disorders with freezing of gait in Parkinson’s disease: A single-arm,open-label,prospective, multicenter study

Background: Gait disorders are common in Parkinson’s disease patients who respond poorly to dopaminergic treatment. Blockade of adenosine A_2A receptors is expected to improve gait disorders. Istradefylline is a first-in-class selective adenosine A_2A receptor antagonist with benefits for motor complications associated with Parkinson’s disease.

Research design and methods: This multicenter, open-label, single-group, prospective interventional study evaluated changes in total gait-related scores of the Part II/III Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) and Freezing of Gait Questionnaire (FOG-Q) in 31 Parkinson’s disease patients treated with istradefylline. Gait analysis by portable gait rhythmogram was performed.

Results: MDS-UPDRS Part III gait-related total scores significantly decreased at Weeks 4–12 from baseline with significant improvements in gait, freezing of gait, and postural stability. Significant decreases in MDS-UPDRS Part II total scores and individual item scores at Week 12 indicated improved daily living activities. At Week 12, there were significant improvements in FOG-Q, new FOG-Q, and overall movement per 48 h measured by portable gait rhythmogram. Adverse events occurred in 7/31 patients.

Conclusions: Istradefylline improved gait disorders in Parkinson’s disease patients complicated with freezing of gait, improving their quality of life. No unexpected adverse drug reactions were identified.

Trial registration: UMIN-CTR (UMIN000020288).     

Treatment of classical Hodgkin’s lymphoma in children and adolescents

Introduction: The treatment of classical Hodgkin lymphoma (cHL) in children is a story of success. Nowadays, more than 90% of patients are cured and overall survival is nearly 100% at 5 years. Efforts have been made to avoid related effects of therapies; therefore, children are treated using different chemotherapy schemes in comparison with adults.

Areas covered: This review includes a view of the clinical classification and risk assessment in children suffering from HL. The chemotherapy more commonly employed is revisited. The use of PET/CT to evaluate the disease in order to guide therapy is analyzed. New options of chemotherapy and emerging immunotherapy are also included.

Expert opinion: In order to make the right treatment choice, a proper initial assessment of risk is mandatory. The choice of therapy in these kinds of patients must be done according to the experience of the team, and also, the cost and logistics related to the eligible scheme are very important. If possible, efforts must be made to include PET/CT in guiding therapy and avoiding overtreatment and long-term adverse effects in children. New options in immunotherapy are emerging and must be considered with caution in selected patients.     

Population pharmacokinetics of oxycodone in plasma and cerebrospinal fluid after epidural and intravenous administration

Objectives: To establish the first plasma and cerebrospinal fluid (CSF) oxycodone population pharmacokinetic (PopPK) model after epidural (EPI) and intravenous (IV) oxycodone administration.

Methods: The study was conducted with 30 female subjects undergoing elective gynecological surgery with epidural analgesia. A parallel single dose of EPI oxycodone with IV placebo (EPI group; n = 18) or IV oxycodone with EPI placebo (IV group; n = 12) was administered. An epidural catheter for drug administration was placed at T12/L1 and a spinal catheter for CSF sampling at L3/4. Plasma and CSF for oxycodone analysis were frequently collected. A PopPK model was built using the NONMEM software package.

Results: Plasma and CSF oxycodone concentrations were evaluated using separate central plasma and CSF compartments and separate peripheral plasma and CSF compartments. Epidural space served as a depot compartment with transfer to both the plasma and CSF central compartments. The population parameters for plasma clearance and apparent distribution volumes for central and peripheral compartments for plasma and CSF were 37.4 L/h, 90.2 L, 68.9 L, 0.035 L (fixed based on literature), and 0.039 L, respectively.

Conclusion: A PopPK model was developed and found to precisely and accurately describe oxycodone time-concentration data in plasma and CSF.     

Routine care interventions with the parents of adult drug and alcohol users

Introduction and aims: To explore routine care interventions which enable parents to support the therapeutic effort of their adult child in drug and alcohol treatment.

Design and methods: Inductive content analysis was used to analyze the experiences of 31 Greek addiction professionals who participated in focus groups.

Findings: Professionals adopted various interventions which included (a) respond to parents quest for help, (b) involvement of the distant parent in treatment, (c) boundary setting, (d) facilitation of parent-child communication, and (e) support of parental changes. These interventions were perceived as necessary, both for motivating and sustaining the client’s change, and for alleviating the parents’ chronic grief and distress over their child’s addiction.

Conclusion: Overall, addiction professionals perceived low intensity interventions, information giving, and non- judgmental informal interactions as catalysts for the parents involvement in addiction treatment.     

Confidentiality and cultural competence? The realities of engaging young British Pakistanis and Bangladeshis into substance use services

Aims: This paper focuses on the reasons for the under-representation of British South Asians in substance use services. Based on a small-scale evaluation of a substance use service that delivers targeted outreach support within two predominantly Pakistani and Bangladeshi communities in the north west of England, this paper contributes to the debate around how substance use services can best engage with young British Pakistani and Bangladeshi substance users.

Methods: Semi-structured interviews (with six staff members, 18 young Pakistani and Bangladeshi service users, and 18 stakeholders and partner agencies), a detailed ethnographic observation of the service, and an analysis of routinely collected quantitative monitoring data.

Findings: The paper highlights the importance of what Fountain terms low threshold/open access services. Alongside this, the paper argues that the building of trust and confidence in a substance use service is a key when it comes to engaging with young Pakistani and Bangladeshi substance users. Yet this necessary process takes time: something that is at odds with the current trend towards short-term funding regimes and ‘quick wins’.

Conclusions: The paper concludes by advocating the need for, not only a diverse range of engagement strategies, but also a longer term approach when it comes to developing and delivering substance use services aimed at successfully engaging with this particular group of substance users.     

Factors that facilitate reporting of adverse drug reactions by pharmacists in Saudi Arabia

Objectives: Adverse drug reactions (ADRs) are a pervasive global problem, and its management is integral to patient safety and healthcare quality. Pharmacists play a pivotal role in monitoring and reporting ADRs, which has a direct impact on patient care. The aim of this study was to identify potential factors that facilitate pharmacists in community and hospital settings to report ADRs.

Methods: A cross-sectional, online survey using a validated questionnaire was administered to pharmacists working in community and hospital pharmacies in Saudi Arabia.

Results: 1,717 community and 153 hospital pharmacists participated in this study. Only 10.2% and 26.8% of community and hospital pharmacists, respectively, admitted ever reporting an ADR. The most reported factors that may facilitate ADRs reporting have included ongoing improvements in therapeutic knowledge about ADRs, attending educational programs with continuous medical education credits, the seriousness of the experienced ADRs and accessibility to patients’ medical profile. The impact of peers by seeing colleagues reporting ADRs and ADRs due to herbal or traditional medicine were the least important factors reported by pharmacists.

Conclusion: The study identified factors that can effectively address the under-reporting of ADRs by pharmacists. A multi-stakeholder, multi-pronged approach of ADR reporting is needed to develop greater awareness of this issue among pharmacists.     

Risk of chemotherapy-induced febrile neutropenia with early discontinuation of pegfilgrastim prophylaxis: a retrospective evaluation using Medicare claims

Background: Two recent evaluations reported that many cancer chemotherapy patients discontinue pegfilgrastim prophylaxis (PP) following the first cycle, and that these patients have a higher subsequent risk of febrile neutropenia (FN). Such evidence is based principally on the experience of younger adults with private healthcare coverage, and the generalizability of results to elderly Medicare patients is unknown.

Methods: A matched-cohort design and data from the Medicare Claims Research Identifiable Files were employed. The source population comprised cancer patients aged ≥65 years who received chemotherapy with intermediate/high-risk for FN and first-cycle PP. From the source population, beginning with the second cycle, all patients who received PP in all previous cycles were identified. From this sub-set, patients who did not receive PP in the cycle of interest (“comparison patients”) were matched to those who received PP in that cycle (“PP patients”); the same process was repeated for subsequent cycles. Odds ratios (OR) for FN (broad and narrow definitions) were estimated using generalized estimating equations.

Results: Among 77,616 elderly patients in the source population, 5.3% did not receive second-cycle PP and were matched to those who did. In cycle 2, FN odds were significantly higher among comparison patients vs PP patients when employing the broad definition (OR?=?1.9, p?<?.001) and the narrow definition (OR?=?2.1, p?<?.001). Results for subsequent cycles (broad definition: OR?=?2.0, p?<?.001; narrow definition: OR?=?2.1, p?<?.001) and for the last cycle (broad definition: OR?=?1.4, p?=?.060; narrow definition: OR?=?1.7, p?=?.055) were largely comparable.

Conclusions: In this large-scale evaluation of elderly Medicare patients who received myelosuppressive chemotherapy and first-cycle PP in recent US clinical practice, FN risk was substantially lower among patients who continued to receive PP in subsequent cycles vs those who discontinued PP.     

Evidence of bioequivalence and positive patient user handling of a tocilizumab autoinjector

Background: The anti–interleukin-6 receptor antibody tocilizumab is approved for subcutaneous injection using a prefilled syringe (PFS). We report results from a bioequivalence study in healthy subjects and a user-handling study in patients with rheumatoid arthritis (RA) using an autoinjector (AI) for tocilizumab.

Methods: A randomized crossover study in healthy subjects (N = 161) examined the bioequivalence, safety, and tolerability of tocilizumab after a single subcutaneous injection by AI versus PFS. A nonrandomized observational, real-life human factors study in RA patients (N = 54) assessed user (RA patients, caregivers, health care providers) ability to administer tocilizumab effectively by AI.

Results: Bioequivalence criteria for tocilizumab AI versus PFS were met for key pharmacokinetic parameters. Safety was comparable between devices and consistent with the established tocilizumab profile. In the real-life human factors study, the proportion of users who successfully performed all essential tasks required to operate the AI to deliver the full dose was 92.3% at first assessment and 98.1% at second assessment, with no safety concerns.

Conclusions: Tocilizumab administration by AI was bioequivalent to administration by PFS. Intended users were successful in performing the tasks required to administer tocilizumab by AI. No new safety signals were observed in either study.

Clinical Trial Registration: NCT02678988, NCT02682823     

Application of disaccharides alone and in combination,for the improvement of stability and particle properties of spray-freeze dried IgG

Purpose: Spray-freeze drying (SFD) is a recently applied method to develop pharmaceutical powders. This study aimed to analyze the competence of Trehalose, Mannitol, Lactose, and Sorbitol instability and aerosolization of Immunoglobulin G (IgG) via SFD.

Methods: Induced soluble aggregates were quantified at 0 and 3?months, and 45?°C using size-exclusion chromatography. Conformation and thermogravimetric assessments were done by Fourier transform infrared spectroscopy and differential scanning calorimetry. Laser light scattering was performed to determine the particle sizes. Aerodynamic features were characterized by twin stage impinger and scanning electron microscopy.

Results: Although sugars/polyols preferably stabilized IgG following the process, storage stabilization was achieved in Trehalose, Trehalose-Lactose, Lactose, and Trehalose-Mannitol-based powders with soluble aggregates <5%. The conformation of antibody was preserved with β sheet content from 66.28% to 76.37%. Particle sizes ranged from 5.23 to 8.12?µm. Mannitol exhibited the best aerodynamic behavior, fine particle fraction (FPF: 70%) but high degree of protein aggregation during storage.

Conclusions: SFD could favorably stabilize antibody using Trehalose and its combination with Lactose and Mannitol, and also, Lactose alone. Sorbitol disturbed IgG powder recovery. Incorporation of other types of excipient is required for efficient respiratory delivery of IgG molecules.     

Comparison of persistence and adherence between fixed-dose combinations and two-pill combinations in Japanese patients with type 2 diabetes

Objective: To compare treatment patterns, persistence and adherence between fixed-dose combinations (FDCs) and two-pill combinations (TPCs) of oral antidiabetic drug (OAD) classes in Japanese patients with type 2 diabetes mellitus (T2DM) using administrative claims databases (Japan Medical Data Center [JMDC] and Medical Data Vision [MDV]).

Methods: This was a retrospective, longitudinal cohort analysis conducted between 2011 and 2015, in patients with T2DM receiving OADs as FDC or TPC. Outcomes included prescribing patterns, treatment persistence and adherence.

Results: Data from 3474 and 3066 patients receiving FDCs, and 4325 and 5192 patients receiving TPCs from the JMDC and MDV databases, respectively, was extracted. The most common OAD combination received by over half of all patients was dipeptidyl peptidase-4 inhibitor (DPP-4i) + thiazolidinediones (TZDs) (64.1% [JMDC] and 70.5% [MDV]). Overall, 12-month persistence rates were higher in patients receiving FDCs compared with TPCs (70.4 vs. 66.2% [JMDC], 75.6 vs. 55.7% [MDV]). In the JMDC population receiving FDCs or TPCs, persistence rates were highest with DPP-4i schedules (67.5–83.5%). Median time to discontinuation was significantly longer with biguanide?+?TZD, and DPP-4i?+?TZD FDC schedules (p < .05) than TPC; adherence rates were ≥80% across all antidiabetic drug classes in both database populations.

Conclusions: Persistence with and adherence to OADs in Japanese patients with T2DM were greater with FDCs than with TPCs, which may suggest increased patient satisfaction due to reduced treatment burden. Further studies are warranted to investigate the impact of adherence and persistence of FDCs of OADs on glycemic control.     

Compliance with clinical guidelines and adherence to antiretroviral therapy among patients living with HIV

Objective: Evaluation of provider compliance with antiretroviral (ARV) treatment guidelines and patient adherence to ARVs is important for HIV care quality assessment; however, there are few current real-world data for guideline compliance and ARV adherence in the US. This study evaluated provider compliance with US Department of Health and Human Services (DHHS) guidelines and patient adherence to ARVs in a US population of patients with HIV.

Methods: This was a retrospective claims study of adults with HIV-1 receiving ARV treatment between January 2010–December 2014. Follow-up began at first ARV treatment and ended at health plan disenrollment or study end. ARV regimens for treatment-naïve patients were categorized as “preferred/recommended”, “alternative”, or “non-preferred/recommended/alternative” according to DHHS guidelines. ARV adherence was evaluated using proportion of days covered (PDC) and medication possession ratio (MPR).

Results: The analysis included 25,320 patients (84.4% male, mean age 45.3 years) and 39,071 regimens. Preferred/recommended regimens were most common during each study year, but the proportion of non-preferred/recommended/alternative regimens was substantial (15.9–20.6%). Only 53.6% of patients had optimal adherence by PDC ≥0.95, and 57.9% by MPR ≥0.95. Guideline non-compliance and sub-optimal adherence were more prevalent among female vs male patients (22.6% vs 14.8% [in 2014] and 65.9% vs 53.7%, respectively).

Conclusions: Provider non-compliance with DHHS guidelines and sub-optimal ARV adherence among patients with HIV remain common in real-world practice, particularly for female patients. Healthcare providers should follow the latest clinical guidelines to ensure that patients receive recommended therapy, and address non-adherence when selecting ARV regimens.     

Utility of food pellets containing 1-aminobenzotriazole for longer term in vivo inhibition of cytochrome P450 in mice

1. The utility of 1-aminobenzotriazole (ABT), incorporated in food, has been investigated as an approach for longer term inhibition of cytochrome P450 (P450) enzymes in mice.

2. In rats, ABT inhibits gastric emptying, to investigate this potential limitation in mice we examined the effect of ABT administration on the oral absorption of NVS-CRF38. Two hour prior oral treatment with 100?mg/kg ABT inhibited the oral absorption of NVS-CRF38, T_max was 4?hours for ABT-treated mice compared to 0.5?hours in the control group.

3. A marked inhibition of hepatic P450 activity was observed in mice fed with ABT containing food pellets for 1?month. P450 activity, as measured by the oral clearance of antipyrine, was inhibited on day 3 (88% of control), week 2 (83% of control) and week 4 (80% of control).

4. T_max values for antipyrine were comparable between ABT-treated mice and the control group, alleviating concerns about impaired gastric function.

5. Inclusion of ABT in food provides a minimally invasive and convenient approach to achieve longer term inhibition of P450 activity in mice. This model has the potential to enable pharmacological proof-of-concept studies for research compounds which are extensively metabolised by P450 enzymes.     

Assessment of bleeding in chronic liver disease and coagulopathy using the IMPROVE bleeding criteria

Background: In this study, the authors utilized the IMPROVE (International Medical Prevention Registry on Venous Thromboembolism) bleeding definition to explore the safety profile of pharmacologic venous thromboembolism (VTE) prophylaxis in patients with chronic liver disease (CLD) and concurrent coagulopathy (INR ≥1.5).

Methods: A retrospective study was conducted on 193 adult patient admissions with a diagnosis of CLD and INR ≥1.5 not due to therapeutic anticoagulation. Patients were stratified based on their receipt of pharmacological thromboprophylaxis or not during hospitalization. The rates of overall bleeding, defined as the composite of major bleeding and clinically relevant non-major bleeding; major bleeding; and clinically relevant non-major bleeding, within 14 days of admission were evaluated. Secondary endpoints included the rates of thrombosis and mortality.

Results: The composite of overall bleeding occurred in 17.6% of the admissions. More patients in the group not receiving pharmacological thromboprophylaxis had overall bleeding (18.5% vs 10%), major bleeding (13.3% vs 10%), and clinically relevant non-major bleeding (14.5% vs 5%), with overlapping 95% CI. When stratified per pharmacological thromboprophylaxis status, IMPROVE bleeding risk score (BRS)?≥?7 was associated with higher rates of overall bleeding, major bleeding, and clinically relevant non-major bleeding as compared to IMPROVE BRS <7, whether patients received or did not receive pharmacological thromboprophylaxis. The overall incidence of in-hospital mortality among our study population was 15.5%. Receiving pharmacological thromboprophylaxis was markedly associated with higher in-hospital mortality (OR?=?16.58, 95% CI?=?4.47–61.45).

Conclusion: This study shows that the IMPROVE BRS calculated on admission may serve as a guide for omission of thromboprophylaxis in advanced CLD.     

Prophylaxis of chemotherapy-induced neutropenia and febrile neutropenia with lipegfilgrastim in 2489 cancer patients: final results from the non-interventional study NADIR

Objectives: The non-interventional study (NIS) NADIR (DRKS00005711) evaluated the effectiveness and safety of prophylaxis with lipegfilgrastim, a glycopegylated granulocyte-colony stimulating factor, in 2500 patients undergoing chemotherapy in routine clinical practice. Primary objective was the incidence of chemotherapy-induced severe neutropenia, febrile neutropenia (FN), and neutropenia-associated complications.

Methods: NADIR was a prospective NIS conducted in 201 study centers in Germany.

Results: The analysis included 2489 patients. Main tumor types were breast cancer (n?=?1198, 48.1%), lung cancer (n?=?303, 12.2%), non-Hodgkin lymphoma (NHL; n?=?337, 13.5%), and prostate cancer (n?=?111, 4.5%). Nine hundred and ten (36.6%) patients were aged ≥65?years (regarded as “elderly” patients). Severe neutropenia (CTCAE grade 3/4) was reported in 26.8% (n?=?666) and 25.2% (n?=?229) of the total population and elderly patients, respectively. FN was documented in 2.7% (n?=?68) of the total population vs 3.0% (n?=?27) of elderly patients. Primary prophylaxis with lipegfilgrastim among patients with high risk of FN (>20%) was documented in 83.5% of the total population and 75.1% of elderly patients. Infections (CTCAE grade 3/4) were documented in 99 patients (4.0%) in the total population vs 47 (5.1%) elderly patients. Fatal infections were reported in 14 (0.6%) patients in the total population vs 11 (1.2%) elderly patients. Overall, most frequent lipegfilgrastim-related adverse events (AEs) included bone pain (8.0%), anemia (3.2%), leucocytosis (2.7%), and thrombocytopenia (2.5%). Of the patients, 18.0% had ≥1 documented serious AE; none of the fatal events (2.7%) was lipegfilgrastim-related.

Conclusions: Lipegfilgrastim administered to patients with solid tumor/NHL undergoing chemotherapy in routine clinical practice showed similar effectiveness and safety compared to the pivotal trials.     

The pharmacologic management of multiple myeloma in older adults

Introduction: Multiple myeloma is a disease predominately affecting older adults. Pivotal to treating older adults is understanding their physiologic differences compared to younger subjects and how the complexity of therapies has an impact upon this patient population.

Areas covered: Herein, the authors address the efficacy of chemotherapy regimens, decision-making for older adults, chemotherapy-associated toxicity and the approach to management. This review focuses on the complex treatment of older multiple myeloma patients and management of treatment-related adverse events.

Expert opinion: Balancing efficacy and managing toxicity is a challenge for older myeloma patients. This group is more susceptible to treatment toxicities due to a higher incidence of pre-existing comorbidities and underlying diminished physiologic reserve. Intensive therapies such as autologous hematopoietic cell transplant (AHCT), however, still should be considered for all multiple myeloma patients, including older adults. The continued development of novel therapies and increased use of multi-drug regimens has changed the treatment paradigms yet understanding the complexity of the aging adult in the context of various drugs is warranted.     

Time course of arsenic species in red blood cells of acute promyelocytic leukemia (APL) patients treated with single agent arsenic trioxide

Background:Arsenic trioxide (ATO) is widely applied to treat acute promyelocytic leukemia (APL). To elucidate metabolism and toxicity of arsenic, we analyzed time course of arsenic species in red blood cells (RBCs) of APL patients.

Methods:Nine APL patients received ATO (0.16 mg/kg/day) through 18-h infusion. Blood was collected before daily administration (days 2 to 9), and at different time points on day 8. Inorganic arsenic (iAs), monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA) were detected by HPLC-ICP-MS.

Results:Arsenic species reached C_max at 18 h on day 8. Arsenicals gradually accumulated during days 2 to 9, whereas their percentages remained almost constant. The general trend in red blood cells (RBCs) was iAs > MMA > DMA. MMA was consistently the predominant methylated arsenic metabolite in RBCs. iAs, MMA, and tAs (tAs = iAs + DMA + MMA) concentrations (P < 0.0001), MMA/DMA ratios (P = 0.0016) and iAs% (P = 0.0013) were higher in RBCs than in plasma.

Conclusions:Time course of arsenic species reveal kinetic characteristic of ATO metabolites in RBCs. Arsenic species accumulated with administration frequency. Arsenic species in RBCs were remarkably different from those in plasma. Time course of arsenic species in RBCs is important in ATO clinical application.     

A clinical perspective on escalating or de-escalating adjuvant therapy in HER2+ breast cancer

Introduction: Patients with early HER2-positive breast cancer (BC) benefit from HER2-targeted systemic therapy. The endorsed standard adjuvant treatment for patients with early HER2-positive breast cancer is chemotherapy plus trastuzumab administered for 1 year.

Areas covered: Several trials have investigated modifications of the standard treatment in terms of de-escalation by either shortening the duration or giving less resource-demanding regimens and in terms of escalation by either adding a second anti-HER2 agent or extending the duration of HER2-targeted treatment for more than 12 months. In this perspective, we would offer a comprehensive view of these trials and discuss their findings.

Expert commentary: At the current state of knowledge, there are still open questions regarding the management of HER2+ BC patients, such as the most adequate duration of trastuzumab therapy, the optimal chemotherapy regimen that should be combined with trastuzumab, and the addition of a second anti-HER2 agent. Growing evidences suggest that some HER2+ BC patients may not need chemotherapy. If these patients could be recognized upfront, optimal response could potentially be reached with HER2-targeted therapy alone.     

Targeted literature review of the humanistic and economic burden of adult growth hormone deficiency

Background: Quality of life (QoL) and health economic data are becoming increasingly important factors in healthcare decision making. While there is a wealth of information establishing the benefit of growth hormone (GH) replacement therapy in adults with growth hormone deficiency (aGHD), recent reviews on the QoL and health economic impact of aGHD and the effect of treatment on these factors is limited.

Objective: The aim of this article is to summarize the impact of early and sustained treatment on the QoL and economic burden of aGHD by conducting a targeted literature review.

Methods: Standard electronic databases, including PubMed and the Cochrane collaboration website, were searched for publications between January 2006 and July 2016 for evidence of the humanistic and economic burden of aGHD. Search terms included growth hormone deficiency, health-related quality of life, HRQoL, patient-reported outcomes, outcome assessment, well-being and adherence.

Results: The literature search identified 732 initial hits and a final 14 publications were included. The analysis showed that the economic burden of aGHD is largely driven by the productivity losses associated with the disease. This is because most patients with aGHD are of working age and the QoL domains (memory & concentration and energy & vitality) most commonly affected by aGHD severely impair a person’s ability to work and may limit their contribution to society.

Conclusion: Untreated aGHD can seriously affect patients’ functioning. Early and continued treatment with GH replacement therapy could potentially improve the QoL and reduce the economic burden associated with aGHD. This review has limitations: only English language articles published since January 2006 were included and many of the studies were conducted in the Nordic countries; it is unclear how representative these studies are of the population as a whole. This was a literature review and not a systematic review, as it was thought to be unlikely that, in this rare disease, any additional publications would have been identified. Overall, this review reveals a paucity of data in this underserved population and points to research gaps which could be addressed with new studies.