Suboptimal Therapy Research Articles

Innovative Collaboration between a Medical Clinic and a Community Pharmacy: A Case Report.

As value-based payments become more common in healthcare, providers can develop collaborative relationships to support performance. A medical clinic and community pharmacy worked together to deliver collaborative medication management services to targeted patients in an accountable care organization. The community pharmacy was paid by the clinic to conduct comprehensive medication reviews (CMRs) for 116 patients. The CMRs initially were delivered to patients taking at least 10 medications and to patients rated as high cost/risk by the clinic. The most common medication-related problem types were Needs additional therapy (38.8%) and Suboptimal therapy (19.0%). The most common pharmacist actions were to Change medication (18.1%) and Initiate new therapy (13.8%). Financial analyses showed net savings in annual patient out-of-pocket expenses just over $15,000 for the cohort of patients, and net annual direct cost savings from a payer perspective of about $70,000. This innovative partnership between a medical clinic system and a regional pharmacy chain built upon initial discussions and planning. The partners were able to address problems that arose with their collaboration, changing their approach as needed. The outcomes were positive for the clinic and pharmacy, their patients and the payer(s). Interested providers are encouraged to pursue similar collaborations, which could be key to success in today’s healthcare environment.

Sequential therapy with sorafenib and regorafenib for advanced hepatocellular carcinoma: a multicenter retrospective study in Japan.

Background Conversion from sorafenib to regorafenib is primarily an evidence-based treatment strategy in patients with advanced hepatocellular carcinoma (HCC). This study aimed to assess the safety and efficacy of sequential therapy with sorafenib and regorafenib in patients with advanced HCC by analysis of outcomes in clinical practice with the aim to complement phase III findings. Methods The medical records of patients with advanced HCC receiving regorafenib were retrieved to collect data on sorafenib administration at seven Japanese institutions. Radiological responses and adverse events were evaluated using the Response Evaluation Criteria in Solid Tumors version 1.1 and the Common Terminology Criteria for Adverse Events version 4.0, respectively. Results Before March 2018, 44 patients were administered regorafenib for advanced HCC. The median sorafenib treatment duration was 8.4months. The most common adverse events were similar to those reported by the RESORCE trial. The median overall survival (OS) was 17.3months (95% confidence interval [CI] 11.4-22.9), and 17 of 37 patients (45.9%) discontinued regorafenib and received sequential systemic therapy after regorafenib. These patients had significantly longer OS than those who were treated by the best supportive care or sub-optimal therapy (not reached versus 8.7months [95% CI 5.8-11.7]; P < 0.001). Conclusion The results based on Japanese clinical practices verified the tolerability of regorafenib in advanced HCC. Major regorafenib-associated adverse events were similar to those related to sorafenib. OS was significantly longer than expected, which might be associated with the sequential systemic therapies after regorafenib, mainly lenvatinib.

PS1402 OUTCOME IN TRANSPLANT ELIGIBLE PATIENTS WITH MULTIPLE MYELOMA IN LATIN AMERICA. AN INTERNATIONAL STUDY OF GELAMM

Background:Multiple myeloma (MM) is a frequent hematologic malignancy. Despite the important advances in treatment strategies during the last decades, the gold standard remains being a proteasome inhibitor (PI)‐based induction, followed by autologous stem cell transplant (ASCT).In Latin America (LA) there is great heterogeneity in access to new drugs and ASCT, and there is scarce data regarding patient́s outcomes in the region.Aims:The aim of this study was to describe clinical characteristics and outcomes of MM transplant eligible patients in LA countries.Methods:Retrospective international multicenter cohort study. Unselected consecutive MM transplant‐ eligible patients diagnosed between 2010 and 2018 from participating centers in Chile, Argentina and Uruguay were included. Data was collected from clinical records in a standardized report form. We analyzed clinical characteristics at diagnosis and frontline therapy outcomes, including ASCT.Transplant‐eligible patients were defined as fit patients younger than 66 years old. Response to treatment was defined according to current IMWG criteria.Statistical analysis was performed by using STATA 13.Results:Six hundred and seventy one patients were included in the study, 282 from Chile, 258 from Argentina and 131 from Uruguay. The main characteristics are shown in Table 1. Significant differences in access to PI induction and ASCT were found between private and public institutions, with patients from the latter receiving suboptimal frontline therapy. Optimal response (sCR, CR and VGPR) was achieved in 51% of the patients in the CyBorD group, in 65% in the VTD group, and in 45% in the CTD group, the 3 main induction regimens used. Only 52% of patients finally underwent ASCT. With a median follow up of 33 months (range 1–109), 5 year overall survival (OS) was 58,4%, with a median survival of 73 months in the whole cohort. When analyzed according to induction treatment, 5 year OS was 74% for PI‐based, 48% for thalidomide‐based, and 23% for those not treated with novel agents (P &lt; 0,0001). In the multivariable analysis, not undergoing ASCT (p &lt; 0,001), renal failure (p = 0,004), hypercalcemia (p = 0,001), and achieving less than VGPR (p = 0,001) response were independent factors associated with worse outcome.Summary/Conclusion:Survival in transplant‐eligible patients is lower than the “optimal” described survival in other regions. Unequal access to PI‐based regimens and therefore to ASCT between public and private centers was observed. Reasons for 48% of candidates not being transplanted merit further analysis.image

PF509 MOLECULAR ANALYSIS OF PRIMARY CUTANEOUS DIFFUSE LARGE B‐CELL LYMPHOMA LEG TYPE AT DIAGNOSIS AND RELAPSE – IMPLICATIONS FOR TARGETED THERAPIES

Background:Primary cutaneous diffuse large B‐cell lymphoma, leg type (PCDLBCL‐LT) is an aggressive cutaneous lymphoma with a 5‐year disease‐specific survival (DSS) of ∼55%. In the past decades, survival hardly improved. Currently, no routine classifiers are available to predict patients at risk for relapsed/refractory disease and to adjust treatment strategies accordingly.Aims:To improve disease classification and risk stratification, we aimed to identify the clinical relevance of advanced molecular profiling in PCDLBCL‐LT.Methods:Using targeted NGS with a 52 B‐cell lymphoma‐related gene panel and stepwise ‘triple FISH’ (MYC/BCL2/BCL6), we investigated skin biopsies of 54 PCDLBCL‐LT patients, at diagnosis (n = 49) and at relapse (n = 20). Sequential analysis was available in 15 cases. Patients were diagnosed in the Leiden University Medical Center, the Netherlands, or the University Hospital Leuven, Belgium, between 2000 and 2019. The obtained profiles were correlated with the clinical characteristics and survival outcomes.Results:The cohort consisted of 54 patients, 27 (50%) females, with a median age at diagnosis of 78 (range 47–92) years. Median follow‐up duration was 81 (range 1–172) months. Additional clinical characteristics are presented in Figure 1. The 5‐year overall survival (OS) was 42% and the DSS 55%. At diagnosis (Figure 1A), highly frequent mutations were seen in MYD88 (69%) and CD79B (51%), both resulting in constitutive activation of the NF‐κB pathway. Other commonly mutated genes were PIM1 (29%), MYC (14%), BTG1 (12%), and TBL1XR1 (10%). MYC rearrangements were present in 26%, including one double hit (BCL6). At relapse (Figure 1B), common mutations were seen in MYD88 (75%), CD79B (55%), PIM1 (35%), MYC (15%), BTG1 (20%), and TBL1XR1 (20%), and MYC was rearranged in 39%. Sequential analysis showed newly obtained mutations in MYC and CD79B (n = 1), PIM1 (n = 2), and PRDM1 (n = 1), and rearrangements in MYC (n = 1) and a double hit in BCL6 (n = 1). In addition, circulating tumor DNA (ctDNA) was detected with digital droplet PCR in 3 of 4 patients harbouring MYD88 L265P, corresponding to the clinical disease status. Female gender and MYC rearrangements, especially in combination with a MYC mutation, showed an inferior OS (gender: p = 0.001, HR 3.88, 95% CI 1.61–9.36; MYC: p = 0.029, HR 1.80, 95% CI 1.06–3.06) and DSS (gender: p = 0.004, HR 6.96, 95% CI 1.97–24.61; MYC: p = 0.004, HR 2.76 95% CI 1.52–5.01) in univariate analysis (Figure 1C‐D). Multivariate analysis demonstrated independent prognostic significance of gender in OS (gender: p = 0.003, HR 4.16, 95% CI 1.63–10.61; MYC: p = 0.137) and both in DSS (gender: p = 0.006, HR 6.04, 95% CI 1.68–21.67; MYC: p = 0.008, HR 3.86, 95% CI 1.42–10.51).Summary/Conclusion:Our data corroborate the importance of the NF‐κB pathway as the major driver of lymphomagenesis in PCDLBCL‐LT, both at diagnosis (82%) and at relapse (90%). Secondly, MYC is commonly involved (26%) and associated with inferior survival. In addition, females had an independently adverse survival compared with males. The molecular profile of primary and relapsed disease largely overlaps without recurrently acquired alterations, suggesting that relapses may result from suboptimal initial therapy. The detection of ctDNA identifies liquid biopsy as a potentially new tool of monitoring treatment response and detecting minimally residual disease. Altogether, these results underline the need for precision medicine in PCDLBCL‐LT patients, with the NF‐κB pathway and MYC as the central targets for novel therapeutic approaches.image

S835 MASS CYTOMETRY REVEAL EARLY SIGNALING RESPONSES TO INDUCTION THERAPY IN IMMUNOPHENOTYPICALLY DEFINED LEUKEMIC CELL SUBSETS THAT PREDICT SURVIVAL IN AML

Background:Current clinical practice in intensive induction treatment of AML recommends morphological response evaluation on day 14–17 after start of induction therapy. (Lowenberg et al NEJM 1999) However, alterations in genes and proteins related to chemotherapy resistance and cell survival can also be detected in vivo within hours after start of therapy. (Gausdal et al Blood 2008, Øyan et al BMC Cancer 2009). The rapid kinetics in cell response to perturbation is underscored by in vitro studies that have shown an immediate response in intracellular signalling networks which can be detected within minutes after cells are exposed to perturbators. (Irish et al 2004).Cytometry by time‐of‐flight (CyTOF) combines the platforms of conventional flow cytometry with mass spectrometry. This dramatically increases the numbers of antibodies that can be analyzed per single cell (&gt;40) and permits a simultaneous analysis of both intracellular signaling networks and phenotypic complexity of AML cells.Aims:Immediate evaluation of intracellular signaling after start of treatment in malignant and non‐malignant cellular subsets could reveal the functional properties of resistant AML cancer clones, and how they may be therapeutically targeted.Methods:We performed a 36‐ dimensional CyTOF analysis of 21 surface markers (CD66b, CD16, CD45, CD11b, CD25, CD3, CD4, CD8, CD56, CD20, CD38, CD34, CD117, CD33, CD64, CD14, HLA‐DR, Axl‐1H12, CD90, CD7, CD123) and 15 intracellular markers (cCaspase‐3, p‐4EB‐P1, p‐Stat 5, p‐Stat 3, p‐Stat 1, p‐p38, p‐ERK ½, p‐Akt, p‐NFkB, p‐CREB, p‐S6, p‐Axl, p‐Rb, Cyclin B1, p‐Histone H3) of 32 de novo AML patients. Peripheral blood was sampled at 4 hours and at 24 hours after start of “7+3” induction therapy (Lowenberg et al Blood 2017). Peripheral blood from healthy donors were also analyzed. Samples were barcoded, and a reference sample was included in each barcode for normalization of potential batch effects. FlowSOM, which applies self‐organizing maps (SOMs), were used to perform unsupervised identification of leukemic and non‐leukemic cell populations across the patient cohort (Van Gassen et al Cytometry A 2015).Results:FlowSOM identified 10 different metaclusters in the 32 AML patients and 7 healthy donors based on well‐ characterized surface markers, as shown in the t‐SNE and heatmap plots (Fig 1B‐C). To identify markers that could predict patient outcome, a lasso regression analysis correlating intracellular signaling markers to patient survival was performed. Basal pre‐treatment signaling levels were not found to be significantly correlated to survival. However, we found that the ratio of pERK 1/2 at 24 hours relative to pre‐treatment in metacluster 9, significantly correlated to overall survival (p = 5,93e−4)(Fig 1D). Thus, an increase in pERK1/2 at 24 hours compared to the pre‐treatment sample, seems unfavorable.Summary/Conclusion:We found that alterations in pERK1/2 during the first 24 hours after start of induction therapy significantly correlated with patient survival. The MAPK/ERK pathway is dysregulated in nearly 50% of all human malignancies and has an important role in cell proliferation, differentiation and survival. Cells with an increase in pERK as response to chemotherapy might represent cancer cell subsets that are resistant to conventional chemotherapy, indicating that ERK could be an interesting therapeutic target in AML. Monitoring of AML patients by CyTOF during therapy seems feasible in a clinical setting, using the therapy as a perturbator for unraveling functional defects in intracellular signaling that could identify suboptimal therapy responders.image

Aproximación diagnóstica al paciente con nefropatía diabética

Changes in the kidney structure and function secondaries to diabetes mellitus are the features characterizing diabetic nephropathy (DN). The most frequent functional alteration is albuminuria, which can evolve to chronic progressive renal disease. Untreated DN or with suboptimal therapy can result in an end-stage chronic renal disease. Risk factors for DN include, among others, genetic predisposition, diabetes duration, wrong blood pressure and glycemic controls. Pathological changes include from mesangial expansion to advanced glomerulosclerosis. The referral to a nephrologist is recommended for those patients with progressive nephropathy or suspicion of non-diabetic renal disease.

Suboptimal T-cell Therapy Drives a Tumor Cell Mutator Phenotype That Promotes Escape from First-Line Treatment.

Antitumor T-cell responses raised by first-line therapies such as chemotherapy, radiation, tumor cell vaccines, and viroimmunotherapy tend to be weak, both quantitatively (low frequency) and qualitatively (low affinity). We show here that T cells that recognize tumor-associated antigens can directly kill tumor cells if used at high effector-to-target ratios. However, when these tumor-reactive T cells were present at suboptimal ratios, direct T-cell-mediated tumor cell killing was reduced and the ability of tumor cells to evolve away from a coapplied therapy (oncolytic or suicide gene therapy) was promoted. This T-cell-mediated increase in therapeutic resistance was associated with C to T transition mutations that are characteristic of APOBEC3 cytosine deaminase activity and was induced through a TNFα and protein kinase C-dependent pathway. Short hairpin RNA inhibition of endogenous APOBEC3 reduced rates of tumor escape from oncolytic virus or suicide gene therapy to those seen in the absence of antitumor T-cell coculture. Conversely, overexpression of human APOBEC3B in tumor cells enhanced escape from suicide gene therapy and oncolytic virus therapy both in vitro and in vivo Our data suggest that weak affinity or low frequency T-cell responses against tumor antigens may contribute to the ability of tumor cells to evolve away from first-line therapies. We conclude that immunotherapies need to be optimized as early as possible so that, if they do not kill the tumor completely, they do not promote treatment resistance.

In vitro potency of antipseudomonal β-lactams against blood and respiratory isolates of P. aeruginosa collected from US hospitals.

Challenges due to multidrug resistant (MDR) Gram-negative bacterial pathogens such as P. aeruginosa (PSA) are increasing globally. Suboptimal antimicrobial therapy of infections caused by PSA is associated with increased morbidity and mortality. As a result, antimicrobial susceptibility (%S) studies are pivotal to identifying trends in antimicrobial resistance that inform decisions regarding choice of antimicrobial therapy. This study assessed the in vitro potency of 7 antipseudomonal agents including ceftolozane/tazobactam (C/T) against PSA collected from numerous sites across the US. Multiple US hospitals provided non-duplicate respiratory and blood isolates of PSA for potency testing. MICs against PSA were determined using broth microdilution methods according to CLSI for 7 antimicrobials with antipseudomonal activity: aztreonam (ATM), cefepime (FEP), ceftazidime (CAZ), C/T, imipenem (IPM), meropenem (MEM) and piperacillin/tazobactam (TZP). %S was defined per CLSI or FDA breakpoint criteria. Thirty-five hospitals geographically spread across the US provided a total of 1,209 PSA isolates. Of the antibiotics assessed, %S to C/T was the highest at 95% with an MIC50 of 0.5 mg/L and MIC90 of 2 mg/L. In comparison, other %S (MIC50/MIC90) was as follows: ATM 66% (8/32); FEP 76% (4/32); CAZ 78% (4/64); IPM 68% (2/16); MEM 74% (0.5/16); and TZP 73% (8/128). For this geographically diverse PSA population, C/T demonstrated the highest overall susceptibility (95%). Other antipseudomonal agents inclusive of the carbapenems displayed susceptibilities of 66-78%. In the era of escalating PSA resistance to the β-lactams, the potency of C/T may represent an important clinical option.

PCN50 CHEAPER BUT AT WHAT PRICE? EXAMPLE OF DECREMENTALLY COST-EFFECTIVENESS ANALYSIS COMPARING MULTI-GENE ASSAYS IN BREAST CANCER

Value-based models are intended to support appropriate use of one procedure/test over another. Cost-ineffective care may nevertheless occur, due to lack of information or to financial incentives. Guidelines state that the 21-gene assay (Oncotype DX®, Genomic Health, Inc.) is the preferred multi-gene assay (MGA) to predict chemotherapy benefit in early stage breast cancer (ESBC). We sought to compute the “decrementally cost-effective” savings (Nelson Ann Intern Med 2009) that might justify substituting another MGA, PAM50-ROR (Prosigna®, NanoString). We conducted a decision analysis using Markov Chain Monte Carlo simulation to estimate posterior distributions in 100,000 women with ESBC. Risk estimates of PAM50-ROR to predict above/below the 21-gene result threshold for chemotherapy benefit (RS=25; Sparano NEJM 2018) were extracted from three published discordance studies. Primary endpoints were: (1) number of women tested with PAM50-ROR recommended adjuvant chemotherapy discordant with 21-gene results (discordant-aCT) and (2) QALY loss from suboptimal therapy choice due to discordance. Incidence of adverse events with chemotherapy, risk of distant recurrence, quality of life effects, and time discounting were based on published estimates (Chandler JCO 2018). The number of women who were discordant-aCT was 23,853 (IQR 16,044 – 26,870) — almost 1 in 5 women tested. The total QALY loss associated with PAM50-ROR versus 21-gene was 24,593 years (IQR 12,265 – 27,161). To be decrementally cost-effective at the $100K threshold, PAM50-ROR would have to save at least $20,000 per patient. Use of appropriate therapy guided by the 21-gene assay reduces distant recurrence incidence and saves costs versus no MGA testing (Hochheiser JCER 2019). Discordant therapy choice resulting from PAM50-ROR use results in QALY losses. PAM50-ROR cannot be decrementally cost-effective, because the required savings is 4× higher than the 21-gene assay price. This case study illustrates that value-based payment models need safeguards to avoid potentially suboptimal substitution of preferred interventions.

Impact of Essential Medicine Stock Outs on Cancer Therapy Delivery in a Resource-Limited Setting.

PURPOSEEssential cancer medicine stock outs are occurring at an increasing frequency worldwide and represent a potential barrier to delivery of standard therapy in patients with cancer in low- and middle-income countries. The objective of this study was to measure the impact of cancer medicine stock outs on delivery of optimal therapy in Botswana.METHODSWe conducted a retrospective analysis of patients with common solid tumor malignancies who received systemic cancer therapy in 2016 at Princess Marina Hospital, Gaborone, Botswana. Primary exposure was the duration of cancer medicine stock out during a treatment cycle interval, when the cancer therapy was intended to be administered. Mixed-effects univariable and multivariable logistic regression analyses were used to calculate the association of the primary exposure, with the primary outcome, suboptimal therapy delivery, defined as any dose reduction, dose delay, missed cycle, or switch in intended therapy.RESULTSA total of 378 patients met diagnostic criteria and received systemic chemotherapy in 2016. Of these, 76% received standard regimens consisting of 1,452 cycle intervals and were included in this analysis. Paclitaxel stock out affected the highest proportion of patients. In multivariable mixed-effects logistic regression, each week of any medicine stock out (odds ratio, 1.9; 95% CI, 1.7 to 2.13; P < .001) was independently associated with an increased risk of a suboptimal therapy delivery event.CONCLUSIONEach week of cancer therapy stock out poses a substantial barrier to receipt of high-quality cancer therapy in low- and middle-income countries. A concerted effort between policymakers and cancer specialists is needed to design implementation strategies to build sustainable systems promoting a reliable supply of cancer medicines.

Diagnostic accuracy and safety of 16α-[18F]fluoro-17β-oestradiol PET-CT for the assessment of oestrogen receptor status in recurrent or metastatic lesions in patients with breast cancer: a prospective cohort study

A biopsy of first recurrence or metastatic disease is recommended to re-evaluate oestrogen receptor status in patients with breast cancer and to select appropriate treatment. However, retesting for oestrogen receptor status with rebiopsy is not always feasible, depending on lesion location and the risk associated with biopsy, and in these cases clinicians continue to treat patients according to the oestrogen receptor status of the primary tumour. Consequently suboptimal therapy might be offered to these patients. We assessed the diagnostic accuracy and safety of 16α-[18F]fluoro-17β-oestradiol (18F-FES) PET-CT to assess oestrogen receptor status in patients with recurrent or metastatic breast cancer. We did a prospective cohort study at the Asan Medical Center, Seoul, South Korea. Eligible patients had breast cancer, with first recurrence or metastatic disease at presentation, were 19 years or older, and had an Eastern Cooperative Oncology Group performance status of 0-2. The primary objective was to show the agreement between qualitative 18F-FES PET-CT interpretation and the results of oestrogen receptor expression by immunohistochemical assay, a non-reference standard test. Whole-body 18F-FES PET-CT imaging was done after intravenous injection of 111-222 MBq of 18F-FES, with dosing primarily determined by radiation dosimetry analysis. 18F-FES uptake above background intensity was interpreted as positive. Efficacy was assessed in all patients with histologically confirmed recurrent or metastatic breast cancer who received 18F-FES and had PET-CT images available (intention-to-diagnose analysis), and safety was assessed in all patients who received 18F-FES. This study is registered with ClinicalTrials.gov, number NCT01986569. Between Nov 27, 2013, and Nov 10, 2016, 93 patients were enrolled. Of the 85 patients included in the efficacy analysis, 47 (55%) were oestrogen receptor-positive and 38 (45%) were oestrogen receptor-negative. Positive status percent agreement between the 18F-FES PET-CT results and oestrogen receptor status by immunohistochemical assay was 76·6% (95% CI 62·0-87·7) and the negative status percent agreement was 100·0% (90·8-100·0). Patients who were oestrogen receptor-positive and had a positive 18F-FES PET-CT result had a significantly higher progesterone receptor expression than those who were oestrogen receptor-positive and had a negative 18F-FES PET-CT result (23 [68%] of 34 patients vs 0 of 11 patients; p<0·0001). The most common adverse event was procedural pain in nine (10%) of 90 patients injected with 18F-FES. No adverse events were related to the study drug except injection site pain in one (1%) patient. No serious adverse events were recorded. The high negative percent agreement between 18F-FES PET-CT and oestrogen receptor status by immunohistochemical assay in this cohort suggests that positive 18F-FES uptake by recurrent or metastatic oestrogen receptor-positive breast cancer lesions could be an alternative to oestrogen receptor assays in this setting. Staging assessment should include 18F-FES PET-CT when retesting oestrogen receptor status is not feasible. Asan Institute for Life Sciences, Ministry of Health and Welfare, South Korea.

TBA225, a fusion toxoid vaccine for protection and broad neutralization of staphylococcal superantigens

Superantigens (SAgs) play a major role in the pathogenesis of Staphylococcus aureus and are associated with several diseases, including food poisoning, bacterial arthritis, and toxic shock syndrome. Monoclonal antibodies to these SAgs, primarily TSST-1, SEB and SEA have been shown to provide protection in animal studies and to reduce clinical severity in bacteremic patients. Here we quantify the pre-existing antibodies against SAgs in many human plasma and IVIG samples and demonstrate that in a major portion of the population these antibody titers are suboptimal and IVIG therapy only incrementally elevates the anti-SAg titers. Our in vitro neutralization studies show that a combination of antibodies against SEA, SEB,and TSST-1 can provide broad neutralization of staphylococcal SAgs. We report a single fusion protein (TBA225) consisting of the toxoid versions of TSST-1, SEB and SEA and demonstrate its immunogenicity and protective efficacy in a mouse model of toxic shock. Antibodies raised against this fusion vaccine provide broad neutralization of purified SAgs and culture supernatants of multiple clinically relevant S. aureus strains. Our data strongly supports the use of this fusion protein as a component of an anti-virulence based multivalent toxoid vaccine against S. aureus disease.

Standards of aminoglycoside therapeutic drug monitoring in a South African private hospital: perspectives and implications.

Therapeutic drug monitoring (TDM) is essential to ensure that aminoglycoside peak concentrations are high enough for effective antimicrobial treatment and trough levels are low enough to minimise toxicity. Inappropriate utilisation of TDM may lead to suboptimal therapy, toxicity and waste of resources. This study aimed to investigate the standard of aminoglycoside TDM performed in adult hospitalised patients. An observational, descriptive, cross-sectional study. A 221-bed private hospital. All patients, older than 18 years, on intravenous aminoglycosides for more than 48 hours were included. None, was observational. A computerised database and patient files were used to obtain the information required for this study. Descriptive statistical analysis was used. Aminoglycoside blood levels and estimated glomerular filtration rate (eGFR) in the patients. One hundred and three (103) patients were included: 65 on gentamicin and 38 on amikacin. Blood levels were performed in only 19 gentamicin (29.23%) and 22 amikacin (57.89%) patients. Trough levels were taken more than 2 hours before the next dose in 12 gentamicin (63.16%) and 12 amikacin (54.54%) patients. The majority of patients (96.92% on gentamicin and 84.21% on amikacin) received once daily doses. TDM was performed in all patients with an estimated glomerular filtration rate (eGFR) lower than 60 mL/min/1.73m2 and in 23.31% of gentamicin patients and 56.76% of amikacin patients with an eGFR higher than 60 mg/min/1.73m2. Incorrect sampling times and unnecessary levels taken in patients with normal renal function indicate a need for aminoglycoside treatment guidelines in the private hospital. None.

Topical issues of prevention, diagnosis and treatment of vulvar and vaginal cancer

Vulvar cancer is a rare malignant tumor with the incidence rate of is 3–8 % of the total incidence of female genital malignant diseases. This disease is the 4th common cause of mortality (after cervical, endometrial and ovarian cancers) and accounts for 18.2 % of the total lethal outcomes. The anatomical structure of the external female organs with their extensive lymphatic and vascular networks contribute to the aggressive course, the trend to metastasize and rapid tumor growth. Progress in the timely diagnosis of vulvar and vaginal cancer is directly linked to increased competence and oncological vigilance among general practitioners and healthcare institutions. It is up to the primary care providers to identify women at risk or at the initial stages of cancer, and refer them to specialized medical facilities for further diagnostics and treatment. The high mortality from these diseases may be linked to the late detection and to the suboptimal therapy, which necessitates further research in this area.

High quality process of care increases one-year survival after acute myocardial infarction (AMI): A cohort study in Italy

BackgroundThe relationship between guideline adherence and outcomes in patients with acute myocardial infarction (AMI) has been widely investigated considering the emergency, acute, post-acute phases separately, but the effectiveness of the whole care process is not known.AimThe study aim was to evaluate the effect of the multicomponent continuum of care on 1-year survival after AMI.MethodsWe conducted a cohort study selecting all incident cases of AMI from health information systems during 2011–2014 in the Lazio region. Patients’ clinical history was defined by retrieving previous hospitalizations and drugs prescriptions. For each subject the probability to reach the hospital and the conditional probabilities to survive to 30 days from admission and to 31–365 days post discharge were estimated through multivariate logistic models. The 1-year survival probability was calculated as the product of the three probabilities. Quality of care indicators were identified in terms of emergency timeliness (time between residence and the nearest hospital), hospital performance in treatment of acute phase (number/timeliness of PCI on STEMI) and drug therapy in post-acute phase (number of drugs among antiplatelet, β-blockers, ACE inhibitors/ARBs, statins). The 1-year survival Probability Ratio (PR) and its Bootstrap Confidence Intervals (BCI) between who were exposed to the highest level of quality of care (timeliness<10', hospitalization in high performance hospital, complete drug therapy) and who exposed to the worst (timeliness≥10', hospitalization in low performance hospital, suboptimal drug therapy) were calculated for a mean-severity patient and varying gender and age. PRs for patients with diabetes and COPD were also evaluated.ResultsWe identified 38,517 incident cases of AMI. The out-of-hospital mortality was 27.6%. Among the people arrived in hospital, 42.9% had a hospitalization for STEMI with 11.1% of mortality in acute phase and 5.4% in post-acute phase. For a mean-severity patient the PR was 1.19 (BCI 1.14–1.24). The ratio did not change by gender, while it moved from 1.06 (BCI 1.05–1.08) for age<65 years to 1.62 (BCI 1.45–1.80) for age >85 years. For patients with diabetes and COPD a slight increase in PRs was also observed.ConclusionsThe 1-year survival probability post AMI depends strongly on the quality of the whole multicomponent continuum of care. Improving the performance in the different phases, taking into account the relationship among these, can lead to considerable saving of lives, in particular for the elderly and for subjects with chronic diseases.

A systematic review and novel classification of listing tools to improve medication in older people

Suboptimal drugs therapy is a threat to older people, and listing tools providing guidance are developed to address this problem. A systematic review was performed to identify and analyze such tools published until February 2018. A novel categorization was developed to separate patient-in-focus listing approaches (PILA) providing disease-related positive and negative guidance from drug-oriented, mostly negative listing approaches (DOLA, DOLA+: with disease specification). In total, 76 tools were identified; only 9 were classified as PILA, 26 as DOLA, and 38 as DOLA+. Three DOLA(+) only address dementia. Most tools were developed in Europe or the USA and address community-dwellers. Thirty-two utilized a Delphi process, and only 10 provide a scoring system. Twenty tools utilize a questionnaire but no structured guidance or answers. Importantly, only 12 interventional clinical trials were identified reporting not only medication quality measures, but also clinical endpoints (e.g. falls, adverse drug reactions, hospitalization). For PILA, 4 trials showed positive, one negative clinical effects of a controlled intervention, for DOLA(+) 1 was positive, 7 negative (Fisher's exact test p < 0.05). An abundance of listing tools has been created. DOLAs that may be applied without intricate patient knowledge prevail over PILAs by sevenfold; unfortunately their clinical validation seems to be far less successful than that of patient-initiated approaches. Drug therapy in older people has to be tailored to their individual, very divergent needs; tools requiring detailed medical knowledge about the patient as the starting point for medication optimization provide the best support.

Strategi monitoring kepatuhan penggunaan antiretroviral pre-exposure prophilaxis pada pasangan serodiscordant

Monitoring strategy of antiretroviral pre-exposure prophylaxis adherence among serodiscordant couple Antiretroviral pre-exposure prophylaxis (PrEP) has been recommended as HIV prevention but poor medical adherence can cause suboptimal therapy. This study explored the strategies of monitoring PrEP adherence among the serodiscordant couples. This systematic review based on 4 data bases (Scopus, Pubmed, Ebsco and Sage Journal), included clinical trial studies articles between 2013-2018, in English, and available in full-text. Papers, which not met the inclusion criteria, will be excluded. Keywords used in this study are ‘serodiscordant couple’ AND ‘method’ OR ‘strategy’ OR ‘approach’ AND ‘pre-exposure prophylaxis intention’ OR ‘pre-exposure prophylaxis adherence’. This study discovered various strategies applied based on the type of delivering process, the variance of dose, and variance of preference of the couple. Preference of PrEP dose and type of application related to heterosexual or homosexual orientation and their social commitment. The paper explains the advantage of M-health and biomarker level monitoring.

Factors associated with intensification of antihypertensive drug therapy in patients with poorly controlled hypertension.

ObjectiveTo assess antihypertensive management of older patients with poor blood pressure (BP) control.MethodsPhysicians, voluntary participating in the study, included six consecutive hypertensive patients during routine visits. Hypertension had to have been previously recognized and averaged office BP was ≥ 140 and/or ≥ 90 mmHg in spite of ≥ 6 weeks of antihypertensive therapy. The physicians completed a questionnaire on patients' history of cardiovascular (CV) risk factors, comorbidities, home BP monitoring, anthropometric data and the pharmacotherapy.ResultsMean age of the 6462 patients was 61 years, 7% were ≥ 80 years, 51% were female. Mean ± SD office BP values were 158 ± 13/92 ± 10 mmHg. The most commonly prescribed antihypertensive drugs were: diuretics (67%), ACE inhibitors (64%), calcium channel blockers (58%) and β-blockers (54%), and their use increased with age. On monotherapy or dual therapy, 43% of the patients and 40% had their latest treatment modification within six months. Home BP monitoring was a factor that accelerated the modification of the therapy. Older patients had to have less chance on faster modification of antihypertensive therapy in spite of presence of diabetes and higher systolic BP.ConclusionsOur study suggests that a large number of outpatients with poor BP control receive suboptimal antihypertensive therapy, especially in primary care. In older patients, higher BP values in the office settings are more frequently accepted by physicians even in case of higher CV risk. Regular home BP monitoring hastens the decision to intensify of antihypertensive treatment.

Intelligent nanoflowers: a full tumor microenvironment-responsive multimodal cancer theranostic nanoplatform.

Although the collaborative therapy of chemotherapy (CT) and photodynamic therapy (PDT) is much more efficient for tumor treatment than monotherapies, premature leakage of drugs from nanocarriers and hypoxia in the tumor microenvironment (TME) result in systemic toxicity and suboptimal therapy efficiency. To overcome these limitations, we developed an intelligent nanoflower composite (termed FHCPC@MnO2) by coating functionalized polyphosphazene on superparamagnetic Fe3O4 nanoclusters and then growing MnO2 nanosheets as an outer shell. The FHCPC@MnO2 nanoflowers with multistage H2O2/pH/GSH-responsive properties could fully exploit TME characteristics, including supernormal glutathione (GSH) levels, low pH and high H2O2, to realize the specific release of drugs in tumors and maximum synergetic therapeutic effects. The MnO2 nanosheets can elevate O2 concentration by catalytic decomposition of H2O2 and can be simultaneously reduced to Mn2+ by overexpressed GSH in the acidic TME. Meanwhile, the inner polyphosphazene containing (bis-(4-hydroxyphenyl)-disulfide) is GSH- and pH-sensitively biodegradable to release the anticancer drug curcumin (CUR) and photosensitizer chlorin e6 (Ce6) in the TME. Therefore, the "triple-responsive" and synergetic strategy simultaneously endows the nanoflowers with specific drug release, relieving hypoxia and the antioxidant capability of the tumor and achieving significant optimization of CT and PDT. In addition, the resulting Mn2+ ions and Fe3O4 core enable in vivo T1/T2 magnetic resonance imaging (MRI), while the released Ce6 can simultaneously provide a fluorescence imaging (FL) function. Unsurprisingly, the intelligent nanoflowers exhibited remarkable multimodal theranostic performance both in vitro and in vivo, suggesting their great potential for precision medicine.

2175. In vitro Potency of Ceftolozane/Tazobactam and Other Antipseudomonal β-Lactams Against P. aeruginosa

BackgroundChallenges due to multidrug resistant Gram-negative bacterial pathogens such as P. aeruginosa (PSA) are increasing globally. Suboptimal antimicrobial therapy of infections caused by PSA is associated with increased morbidity and mortality. As a result, antimicrobial susceptibility (%S) studies are pivotal to identifying trends in antimicrobial resistance that inform decisions regarding choice of antimicrobial therapy. This study assessed the in vitro potency of 7 antipseudomonal agents including ceftolozane/tazobactam against PSA collected from numerous sites across the United States.MethodsMultiple U.S. hospitals provided nonduplicate respiratory and blood isolates of PSA for potency testing. MICs against PSA were determined using broth microdilution methods according to CLSI for seven antimicrobials with antipseudomonal activity: aztreonam, cefepime, ceftazidime, ceftolozane/tazobactam, imipenem, meropenem and piperacillin/tazobactam. Susceptibility (%S) was defined per CLSI or FDA breakpoint criteria.ResultsFourteen hospitals geographically spread across the United States provided total of 560 PSA isolates. Of the antibiotics assessed, %S to C/T was the highest at 95% with an MIC50 of 1 µg/mL and MIC90 of 2 µg/mL. In comparison, other %S (MIC50/MIC90) were as follows: ceftazidime 76% (4/64); cefepime 75% (4/32); piperacillin/tazobactam 73% (8/128), meropenem 72% (0.5/16); aztreonam 65% (8/32) and imipenem 65% (2/16).ConclusionFor this geographically diverse PSA population, ceftolozane/tazobactam demonstrated the highest overall susceptibility (95%). Other antipseudomonal agents inclusive of the carbapenems displayed susceptibilities of 65–76%. In the era of escalating PSA resistance to the β-lactams, the potency of ceftolozane/tazobactam may represent an important clinical option.Disclosures D. P. Nicolau, Merck: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Speaker honorarium.