Median Response Rate Research Articles

Characteristics of cardiac rehabilitation programs in Latin America and the Caribbean, and estimation of capacity and needs in the region

Abstract Background Cardiac rehabilitation (CR) is an established model of cardiovascular (CV) prevention that has proven benefits. Availability, characteristics and need of CR programs in Latin-American and Caribbean (LAC) countries remains poorly characterized. This study aims to establish the availability, capacity, density and aspects of CR delivery in LAC. Methods A cross-sectional survey was administered to CR programs in 24 LAC. Local CV organizations and societies identified CR programs. Characteristics of individual CR program were reviewed including: funding sources, core components, healthcare providers, and dose (number of sessions per weeks X total number of weeks) of CR. National CR capacity (median number of patients a program could serve per year X number of programs per country), density (Ischemic Heart Disease [IHD] incidence per year/ national capacity), need (IHD incidence per year- national capacity) and occupancy (median number patients program served per year/national capacity) were computed based on survey responses. Results At least one CR program was identified per LAC country (total 255 programs across 24 countries). Data was collected in 20 of the 24 countries. Responses were received from 139/255 programs (median program response rate=55%; Table 1). Over 50% (n=73) of programs were funded by multiple sources (government, hospital/clinic, private health insurance); Self-payment was reported by 63% programs, in which 24 (33.8%) patients paid over 50% of the cost. Guideline-indicated conditions were accepted in 77% or more programs. Physiotherapists (n=106, 76.3%), cardiologists (n=105, 75.5%) and dietitians (n=79, 56.8%) were the most common healthcare providers on CR teams. Regionally, programs offered 9 (IQR = 8–10) core components (patient education, exercise prescription and initial assessment delivered by nearly all programs). Median CR was 36 (IQR = 24–56) sessions/patient. Twenty-seven (20.9%) programs offered alternative CR models (e.g., home or community-based and hybrid models). Median national capacity was 500 CR spots/country (IQR= 200–2300). Regional density was 1 CR spot per 24 incident IHD patients per year. Greatest need in absolute terms for CR was observed in Brazil, Dominican Republic and Mexico (all with >150,000 spots needed per year to manage incident IHD patients; Table 1). Occupancy ranged from over 100% in Colombia to 15% in Chile (median=60%, IQR = 32%–81%), Table 1. Conclusion In LAC countries, there is very limited capacity to meet the need for CR. Nature of CR services varied regionally. Funding Acknowledgement Type of funding source: None

Lifetime Prevalence of Cervical Cancer Screening in 55 Low- and Middle-Income Countries

The World Health Organization is developing a global strategy to eliminate cervical cancer, with goals for screening prevalence among women aged 30 through 49 years. However, evidence on prevalence levels of cervical cancer screening in low- and middle-income countries (LMICs) is sparse. To determine lifetime cervical cancer screening prevalence in LMICs and its variation across and within world regions and countries. Analysis of cross-sectional nationally representative household surveys carried out in 55 LMICs from 2005 through 2018. The median response rate across surveys was 93.8% (range, 64.0%-99.3%). The population-based sample consisted of 1 136 289 women aged 15 years or older, of whom 6885 (0.6%) had missing information for the survey question on cervical cancer screening. World region, country; countries' economic, social, and health system characteristics; and individuals' sociodemographic characteristics. Self-report of having ever had a screening test for cervical cancer. Of the 1 129 404 women included in the analysis, 542 475 were aged 30 through 49 years. A country-level median of 43.6% (interquartile range [IQR], 13.9%-77.3%; range, 0.3%-97.4%) of women aged 30 through 49 years self-reported to have ever been screened, with countries in Latin America and the Caribbean having the highest prevalence (country-level median, 84.6%; IQR, 65.7%-91.1%; range, 11.7%-97.4%) and those in sub-Saharan Africa the lowest prevalence (country-level median, 16.9%; IQR, 3.7%-31.0%; range, 0.9%-50.8%). There was large variation in the self-reported lifetime prevalence of cervical cancer screening among countries within regions and among countries with similar levels of per capita gross domestic product and total health expenditure. Within countries, women who lived in rural areas, had low educational attainment, or had low household wealth were generally least likely to self-report ever having been screened. In this cross-sectional study of data collected in 55 low- and middle-income countries from 2005 through 2018, there was wide variation between countries in the self-reported lifetime prevalence of cervical cancer screening. However, the median prevalence was only 44%, supporting the need to increase the rate of screening.

Lymphatic malformations in children: treatment outcomes of sclerotherapy in a large cohort

This retrospective study examines the outcomes of sclerotherapy in children with (veno)lymphatic malformations who received sclerotherapy between 2011 and 2016 (116 children, 234 procedures). Complication severity was classified using the Society of Interventional Radiology classification. Clinical response was rated on a scale of 0 (no change) to 3 (good improvement). The sclerosants used were bleomycin (n = 132; 56%), lauromacrogol (n = 42; 18%), doxycycline (n = 15; 6%), ethanol (n = 12; 5%), or a combination (n = 33; 14%). Four major and 25 minor complications occurred without significant differences between the agents. The median response rate per procedure was 2—some improvement—for all sclerosants. However, in pure LMs (67%), bleomycin and a combination of agents resulted in the best clinical response. On patient level, all had some or good clinical response. Mixed macrocystic and microcystic lesions showed a significantly lower clinical response (median 2 versus 3; p = 0.023 and p = 0.036, respectively) and required significantly more procedures (median 2 versus 1; p = 0.043 and p = 0.044, respectively) compared with lesions with one component.Conclusion: Sclerotherapy for (V)LMs in children is safe and effective. Bleomycin is the most frequently used agent in this clinic and seemed most effective for pure LMs. Mixed macrocystic and microcystic lesions are most difficult to treat effectively.What is Known:• A variety of agents can be used for sclerotherapy of lymphatic malformations in children.• Macrocystic lesions have favorable outcomes compared with microcystic and mixed lesions.What is New:• Bleomycin and a combination of agents seem to be most effective to treat lymphatic malformations in children.• Mixed macrocystic and microcystic lesions are more difficult to treat effectively compared with lesions with either one of these components.

Patient-centered Weight Tracking as an Early Cancer Detection Strategy.

Early detection is a valued strategy to decrease cancer mortality rates; however, new strategies are needed. Unintentional weight loss (UWL) is experienced by patients across the cancer spectrum, but often goes unnoticed. Patient-centered weight tracking may be a useful early detection marker. Fifty patients were enrolled in a prospective patient-centered weight tracking trial. Patients received a scale and monetary compensation to participate. A reminder to measure and record weight was texted to participants for 26 consecutive weeks. Most patients were black (86.0%) and female (68.0%). The median age was 47 years (range: 22-84 years). Many participants had Medicaid (42.0%) and the median household income by home zip code was $31,046. After 26 weeks, 90% of patients had recorded at least one weight. Among all patients, 73.7% of all possible weights were recorded and the median response rate per patient was 92.3% (24 of 26 weights). There was no difference in the response rates during the first and second halves of the study (77.7% vs. 69.7%, P = 0.53). The range of weight change over the study period was 16.1% loss to 25.0% gain, with 56% of patients maintaining stable weight. Seven patients (14.0%) lost more than 5% weight and 11 patients (22.0%) gained over 5%. Of the seven patients with weight loss, two (4.0% of the cohort) were determined to have UWL. Patient-centered weight tracking is feasible and inexpensive, and has potential as an early detector of UWL. Further studies are needed to apply this strategy to detect underlying malignancies.

Knowledge, Behaviors, and Attitudes Regarding Venous Thromboembolism Prophylaxis: A Survey of Clinicians at a Tertiary Hospital of China

In this study, we sought to assess knowledge, attitudes, and behaviors regarding venous thromboembolism (VTE) prophylaxis among clinicians at a tertiary hospital of China. An electronic questionnaire was sent to clinicians to gather information regarding demographic data (5 items), knowledge about VTE prophylaxis (21 items), behaviors regarding VTE prophylaxis (8 items), and attitudes regarding VTE prophylaxis (7 items). Answers of "strongly agree" and "agree" on the behaviors and attitude items were defined as affirmative responses. Clinicians were also asked to provide suggestions regarding VTE prophylaxis. A total of 867 clinicians were included in this study. The overall correct response rate for knowledge items was 60.9%. The median affirmative response rate for behavior items was 48.6% (range 29.5-80.3%), and the median affirmative response rate for attitude items was 98.7% (range 96.9-99.3%). Clinicians were most concerned about the adverse effects triggered by chemical VTE prophylaxis (79.5%) and possibility of a financial penalty when a patient could not be treated with VTE prophylaxis (72.3%). Low patient compliance and low level of clinician knowledge and participation were identified most commonly as difficulties involved in VTE prophylaxis. A total of 78 suggestions were collected; these suggestions generally focused on improving the quality and frequency of staff training (n=24) and enhancing learning opportunities (n=22). Although the clinicians' overall attitude toward VTE prophylaxis was positive, the knowledge level was relatively poor, and the rate of affirmative responses regarding behaviors was low. Medical institutions should improve clinician training regarding VTE prophylaxis.

A Text Messaging Intervention With Financial Incentive for Adolescents With Type 1 Diabetes

Adolescents with type 1 diabetes (T1D) have higher hemoglobin A1C (HbA1c) levels than others. In general, adolescents engage with text messaging (TM) and financial incentives, both associated with improved diabetes outcomes. This study aimed to assess the impact of a TM intervention with financial incentives on self-care behaviors and HbA1c. A six-month randomized controlled trial compared MyDiaText™, a TM education and support application, with standard care. The sample included 166 teens with T1D, 12-18 years old, attending a diabetes clinic. The intervention group received one daily TM and were instructed to respond. Participants who responded to TMs for the most consecutive days were eligible for a financial reward biweekly via lottery. All participants received prompts to complete the self-care inventory (SCI) at baseline, 90, and 180 days. HbA1c was collected at clinic visits. Changes in SCI and HbA1c were analyzed using a multilevel mixed-effects linear regression model. Intention-to-treat and per-protocol analyses were performed. The median TM response rate was 59% (interquartile range 40.1%-85.2%) and decreased over time. After adjustment for baseline characteristics, in per-protocol analysis, there was a statistically significant difference in SCI score increase in those receiving one TM per day vs control (P = .035). HbA1c decreased overall, without significant difference between groups (P = .786). A TM intervention with financial incentives for adolescents with T1D in suboptimal control was associated with increasing self-care report; however, glycemic control did not differ from controls. Further research is needed to develop digital health interventions that will impact glycemic control.

Abstract 5639: NT219, a novel dual inhibitor of STAT3 and IRS1/2, demonstrates anti-tumor activity with and without cetuximab in pembrolizumab-resistant head and neck cancer PDX models

Abstract Background: Pembrolizumab with chemotherapy is approved as first line therapy for recurrent and metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). Patients refractory to this regimen are often treated with cetuximab. Historically, cetuximab monotherapy resulted in a median response rate of ~13% and an overall survival of ~6 months in patients with platinum-resistant R/M HNSCC. Better therapies for this population are therefore highly warranted. Insulin Receptor Substrate 1 and 2 (IRS1/2) and STAT3 are major signaling junctions regulated by various oncogenes and altered during epithelial-to-mesenchymal transition and drug resistance. Feedback activation of STAT3 and IGF1R/IRS plays a prominent role in mediating drug resistance to EGFR blockers. STAT3 has also been demonstrated to play an active role in tumor's immune evasion. NT219 is a novel small molecule dual inhibitor of IRS1/2 and STAT3. The purpose of this study was to evaluate NT219 anti-tumor activity with and without cetuximab in pembrolizumab-resistant head and neck cancer PDX models. Methods: Mice were inoculated with biopsies from naïve or platinum and anti-PD1 treated head and neck cancer patients. PBMCs or CD34+ cells from the same patient from whom the biopsy was obtained, were injected to allow immune system involvement in the anti-tumoral effect. Immunoblotting, immunohistochemistry and FACS analyses were used to assess the pharmacodynamic effect of NT219 and to explore mechanism of action. Results: HNSCC cells treated with NT219 demonstrated elimination of IRS1/2 and dephosphorylation of STAT3. A short exposure to NT219 induced prolonged inhibition of both IRS and STAT3 and resulted in cancer cell apoptosis. In PDX models of the head and neck cancer, NT219 induced tumor growth inhibition and regression as a monotherapy (3/6), and in combination with cetuximab or pembrolizumab (5/6), respectively. Of particular interest was a model, which originated from a biopsy of R/M HNSCC patient previously treated and progressed on radiation, various chemotherapies, and pembrolizumab, where autologous PBMC's were injected. Administration of NT219 as a monotherapy resulted in tumor growth inhibition (TGI) of 69% (p-value=0.017). In combination with cetuximab, NT219 induced regression of all tumors. While cetuximab alone demonstrated modest TGI (17%), the addition of NT219 showed synergistic effect and complete TGI (p-value=0.001). Similar results were obtained in a repeated experiment where CD34+ cells were used. Conclusion: NT219 induced tumor regression of R/M HNSCC and sensitized resistant tumors to cetuximab and pembrolizumab. The unique mechanism of NT219, targeting two central mechanisms involved in cancer drug resistance, supports further clinical development of NT219 which may present an attractive 2nd and 3rd line therapy. Citation Format: Hadas Reuveni, Lana Kupershmidt, Emmanuelle Merquiol, Galia Blum, Ohad Ronen, Izhak Haviv. NT219, a novel dual inhibitor of STAT3 and IRS1/2, demonstrates anti-tumor activity with and without cetuximab in pembrolizumab-resistant head and neck cancer PDX models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5639.

<p>Quality and Impact of Survey Research Among Anesthesiologists: A Systematic Review</p>

New technology has facilitated survey research of anesthesia professional society members. We evaluated prevailing metrics of quality and impact of published research studies based on surveys of anesthesiologists. We hypothesized that adherence to recommended practices (such as use of reminders) would be associated with increased survey response rates, and that higher response rates would be associated with higher article impact. Using the MEDLINE database, we identified 45 English-language research articles published in 2010–2017 reporting original data from surveys of anesthesiologists. The median response rate was 37% (IQR: 25–46%). Recommended survey practices, including the use of reminders (p = 0.861) and validated questionnaires (p = 0.719), were not correlated with response rates. In turn, survey response rates were not associated with measures of article impact (p = 0.528). The impact of published research based on surveys of anesthesiologists, as measured by citation scores (p = 0.493) and Altmetrics (p = 0.826), may be driven primarily by the novel data or questions raised using survey methodology, but does not appear to be associated with response rates. Improving reporting of survey methodology and understanding possible sources of non-response bias are important for future studies in this area.

Combining cellular immunotherapy was an optional choice for unresectable advanced HCC: A systematic review and meta-analysis

The efficacy of cellular immunotherapy in advanced hepatocellular carcinoma (HCC) was controversial. This study was conducted to compare the effectiveness of combining cellular immunotherapy with that of incurable treatment alone. The Ovid Medline, Embase, Cochrane Library and Pubmed were systematically searched due to January 8th 2020. The keywords include "immunotherapy", "HCC" and study type. Treatment response was evaluated and progression-free survival (PFS) and overall survival (OS) were calculated using hazard ratio (HR) and 95% confidence interval (CI). A total of 19 studies with 1275 patients were included in the meta-analysis. The median complete response rate (CR) was 19% in combining cellular immunotherapy comparing to 9% in the control group (RR=0.55, P=0.003). No significant difference was found in partial response and stable disease (RR=1.06 and 0.78, P>0.05, respectively). The progression disease rate was higher in the non-cellular immunotherapy group (31%) compared to the cellular immunotherapy group (RR=2.20, P=0.002). Patients treating with cellular immunotherapy had a better OS and PFS compared to those without cellular immunotherapy (HR=0.52 and 0.63, P<0.001). In the subgroup analysis, the only CIK infusion therapy and combined DC with CIK perfusion therapy patients had a better OS (HR=0.52 and 0.49, P<0.001 and P=0.002, respectively). Our results suggested that combining use of cellular immunotherapy in advanced HCC could increase the complete response rate, and thereafter extend the progression-free and overall survival rate. Subgroup analysis suggested that combining use of CIK and DC or using CIK alone could provide the benefit in survival outcome.

User Engagement Among Diverse Adults in a 12-Month Text Message-Delivered Diabetes Support Intervention: Results from a Randomized Controlled Trial.

BackgroundText message–delivered interventions are a feasible and scalable approach for improving chronic disease self-care and reducing health disparities; however, information on long-term user engagement with these interventions is limited.ObjectiveThe aim of this study is to examine user engagement in a 12-month text message–delivered intervention supporting diabetes self-care, called REACH (Rapid Education/Encouragement And Communications for Health), among racially and socioeconomically diverse patients with type 2 diabetes (T2D). We explored time trends in engagement, associations between patient characteristics and engagement, and whether the addition of a human component or allowing patients to change their text frequency affected engagement. Qualitative data informed patients’ subjective experience of their engagement.MethodsWe recruited patients with T2D for a randomized trial evaluating mobile phone support relative to enhanced treatment as usual. This analysis was limited to participants assigned to the intervention. Participants completed a survey and hemoglobin A1c (HbA1c) test and received REACH text messages, including self-care promotion texts, interactive texts asking about medication adherence, and adherence feedback texts. For the first 6 months, texts were sent daily, and half of the participants also received monthly phone coaching. After 6 months, coaching stopped, and participants had the option to receive fewer texts for the subsequent 6 months. We defined engagement via responses to the interactive texts and responses to a follow-up interview. We used regression models to analyze associations with response rate and thematic and structural analysis to understand participants’ reasons for responding to the texts and their preferred text frequency.ResultsThe participants were, on average, aged 55.8 (SD 9.8) years, 55.2% (137/248) female, and 52.0% (129/248) non-White; 40.7% (101/248) had ≤ a high school education, and 40.7% (101/248) had an annual household income <US $25,000. The median response rate to interactive texts was 91% (IQR 75%-97%) over 12 months. Engagement gradually declined throughout the intervention but remained high. Engagement did not differ by age, gender, education, income, diabetes duration, insulin status, health literacy, or numeracy. Black race and worse baseline medication adherence and HbA1c were each associated with lower engagement, although the effects were small. Nearly half of the participants chose to continue receiving daily texts for the last 6 months of the intervention. Participants who continued daily text messages said they wanted to continue experiencing benefits to their health, whereas those who chose fewer texts said that the daily texts had helped them create routines and they no longer needed them as often. Engagement was not impacted by receiving coaching or by participants’ chosen text frequency.ConclusionsWell-designed interactive text messages can engage diverse patients in a self-care intervention for at least 1 year. Variation in and reasons for frequency preference suggest that offering a frequency choice may be important to users’ engagement.

Transarterial chemoembolization combined with iodine 125 seeds versus transarterial chemoembolization combined with radiofrequency ablation in the treatment of early- and intermediate-stage hepatocellular carcinoma

BackgroundTransarterial chemoembolization (TACE), radiofrequency ablation (RFA), and iodine 125 seeds implantation are optional treatments for hepatocellular carcinoma (HCC). The aim of this study is to compare the efficacy of the combined treatment of TACE with iodine 125 seeds implantation (TACE-iodine 125) with TACE with RFA (TACE-RFA) in patients with early- and intermediate-stage HCC.MethodsThe study included 112 patients who were diagnosed with early- and intermediate-stage HCC from January 1, 2014, to May 31, 2018. Among them, 38 patients were treated with TACE-Iodine 125, and 74 with TACE-RFA. The efficacy of the two treatment groups was retrospectively analyzed. To reduced the selective bias, a propensity score matching (PSM) analysis and inverse probability of treatment weighting (IPTW) method were used to compare the outcomes between the two groups.ResultsIn the absence of PSM and IPTW, the median overall survival (OS) and progression-free survival (PFS) of the TACE-RFA group were slightly longer than those of the TACE-Iodine 125 group (OS: 41 months vs. 36 months; PFS: 18 months vs. 15 months). However, there were no statistically significant differences in the median OS, PFS, and objective response rate (ORR) between the two groups (P > 0.05). After adjusting the age, gender, Child-Pugh class, Barcelona Clinic Liver Cancer (BCLC) stage, and Alpha-fetoprotein (AFP), TACE-Iodine 125 treatment was not associated with a significant increasing the risks of death (HR: 0.763; 95%CI: 0.403,1.345, P = 0.320) and recurrence (HR: 1.020; 95%CI: 0.645,1.611, P = 0.934). After PSM, 35 matched pairs of patients were obtained, and there were no statistically significant differences in the median OS and PFS between the two groups. After IPTW, similar results presented.ConclusionsThe combination of TACE with iodine 125 seeds implantation may represent an effective treatment for patients with early- and intermediate-stage HCC.

A Phase I Study of Ribociclib Plus Everolimus in Patients with Metastatic Pancreatic Adenocarcinoma Refractory to Chemotherapy.

Purpose: Metastatic pancreatic adenocarcinoma (mPC) has a poor prognosis. CDK4/6 is often deregulated in mPC due to CDKN2A loss, resulting in the loss of p16INK4a that inhibits CDK4/6. CDK4/6 inhibitor monotherapy is ineffective due to RAS-mediated activation of alternative pathways, including phosphatidylinositol 3-kinase–mammalian target of rapamycin (PI3K-mTOR). We conducted a phase I study combining CDK4/6 and mTOR inhibition in patients with mPC refractory to standard chemotherapy.Materials and Methods: The combination of ribociclib (a CDK4/6 inhibitor) and everolimus (an mTOR inhibitor) was investigated in a phase I study in patients with mPC and progression on 5-fluorouracil- and gemcitabine-based chemotherapy. A 3 + 3 design was used to find the recommended phase II dose (RP2D) of ribociclib (250 or 300 mg daily for days 1–21) in combination with everolimus (2.5 mg daily for days 1–28) every 28 days. Secondary endpoints were median progression-free survival (mPFS), median overall survival (mOS), response rate, safety, and effect on the retinoblastoma pathway.Results: Twelve patients were enrolled, six at each dose level. Only one patient had a dose-limiting toxicity of a grade 3 rash at the 250 mg dose. The RP2D of ribociclib was 300 mg. mPFS was 1.8 months (95% confidence interval [CI] [0.6–2.1]), and mOS was 3.7 months (95% CI [2.3–5.6]). Two patients (17%) had stable disease at 8 weeks. Pharmacodynamic evaluation demonstrated that CDK4/6-regulated gene expression was significantly decreased on treatment (n = 6, p < 0.001).Conclusion: Ribociclib 300 mg daily for days 1–21 plus everolimus 2.5 mg daily was well tolerated and associated with decreased CDK4/6-regulated gene expression. This combination was not effective as a third-line therapy but does pharmacologically target CDK4/6 in mPC, revealing the potential for benefit in other settings.

Evaluation of minimal residual disease in relapsed/refractory multiple myeloma patients treated with venetoclax or placebo in combination with bortezomib and dexamethasone: BELLINI study analyses.

8547 Background: Venetoclax (Ven) is a selective, potent BCL-2 inhibitor that has synergistic activity with bortezomib (B) and dexamethasone (d). In the Phase 3 BELLINI trial, addition of Ven to Bd significantly improved median progression-free survival (PFS) and response rates, including minimal residual disease (MRD) negativity, but resulted in increased mortality vs placebo (Pbo). Here, we determine whether MRD negativity was associated with longer PFS and OS in relapsed/refractory multiple myeloma (RRMM) patients treated with Ven+Bd in the BELLINI dataset. Methods: In BELLINI (NCT02755597), RRMM patients (pts) sensitive or naïve to proteasome inhibitors with 1-3 prior lines of therapy were randomized 2:1 to Ven (800 mg) or Pbo plus B (1.3 mg/m2) and d (20 mg). Next-gen sequencing MRD assessments were done on bone marrow aspirates at the time of suspected CR/sCR, and 6- and 12-months post confirmation of CR/sCR. Patients with a missing or indeterminate assessment were considered MRD positive. Evaluation of MRD in biomarker-defined subgroups (cytogenetics and BCL2 expression) was also performed and will be presented. Results: In total, 291 pts were randomized; 194 to Ven, 97 to Pbo. As of 13 Sep 2019, the median follow-up was 29 months. Ven + Bd demonstrated significantly higher MRD negativity rates ( &lt; 10−5), including a higher proportion of pts achieving sustained MRD negativity (Table). In the Ven arm, the median (m)PFS was not reached for MRD negative pts vs 16.2 months for MRD positive pts (HR = 0.23, 95% CI: 0.10-0.54, p &lt; 0.001). While the mOS was not reached in the Ven arm, OS was significantly longer for MRD negative vs MRD positive pts (HR = 0.25, 95% CI: 0.08-0.80, p = 0.0194). Conclusions: The addition of Ven to Bd resulted in deep and durable responses, including higher rates of MRD negativity. MRD negativity in the context of Ven was associated with prolonged survival in patients with RRMM, consistent with the broader MRD body of evidence with other therapies in MM. Clinical trial information: NCT02755597 . [Table: see text]

Randomised phase II trial of gemcitabine and nab-paclitaxel with necuparanib or placebo in untreated metastatic pancreas ductal adenocarcinoma

BackgroundNecuparanib, a rationally engineered low-molecular-weight heparin, combined with gemcitabine/nab-paclitaxel showed an encouraging safety and oncologic signal in a phase Ib trial. This randomised multicentre phase II trial evaluates the addition of necuparanib or placebo to gemcitabine/nab-paclitaxel in untreated metastatic pancreatic ductal adenocarcinoma (PDAC). Patients and methodsEligibility included 18 years, histologically or cytologically confirmed metastatic PDAC, measurable disease and Eastern Co-Operative Oncology Group performance status of 0–1. Patients were randomly assigned to necuparanib (5 mg/kg subcutaneous injection once daily) or placebo (subcutaneous injection once daily) and gemcitabine/nab-paclitaxel on days 1, 8 and 15 of 28-day cycles. The primary end-point was median overall survival (OS), and secondary end-points included median progression-free survival, response rates and safety. ResultsOne-hundred ten patients were randomised, 62 to necuparanib arm and 58 to placebo arm. The futility boundary was crossed at a planned interim analysis, and the study was terminated by the Data Safety Monitoring Board. The median OS was 10.71 months (95% confidence interval [CI]: 7.95–11.96) for necuparanib arm and 9.99 months (95% CI: 7.85–12.85) for placebo arm (hazard ratio: 1.12, 95% CI: 0.66–1.89, P-value: 0.671). The necuparanib arm had a higher incidence of haematologic toxicity relative to placebo patients (83% and 70%). ConclusionThe addition of necuparanib to standard of care treatment for advanced PDAC did not improve OS. Safety was acceptable. No further development of necuparanib is planned although targeting the coagulation cascade pathway remains relevant in PDAC. NCT01621243

Relationship Between Response and Dose in Published, Contemporary Phase I Oncology Trials.

As progress continues in oncology drug development, this study aimed to examine whether the previously established association between drug dose and efficacy in the era of cytotoxic therapies remains true in today's phase I dose-escalation oncology trials. A systematic review of early-phase dose-finding trials of single-agent oncology drugs from 2015 to 2018 was conducted to examine the relationship between drug dose and objective responses. Cancer-specific trials were included if they determined maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D). Data related to the study drug, study design, treatment response, cancer type, dose levels, MTD, and RP2D were all collected. Dose level was categorized into 4 categories (≤40%, 41%-80%, 81%-120%, and >120% of the RP2D) and was further analyzed by class of drug. A total of 175 phase I studies were identified, with a total of 7,330 patients showing a median response rate of 5% (range, 0%-83%) across trials. A total of 93 trials with 2,506 participants had response data corresponding to drug dose level. In this subset, the median response rate was 5% (range, 0%-83%) across trials. Across all participants in this subset, the response rate was 12% (57 of 491) among those in the dose range of ≤40% of RP2D, 17% (95 of 562) among those in 41% to 80% of RP2D, 23% (272 of 1,206) among those in 81% to 120% of RP2D, and 29% (71 of 247) among those in >120% of RP2D (P<.001). The response rate at ≤40% of RP2D for targeted antibody was 5%, 4% for cellular therapy, 19% for immunotherapy, and 21% for small-molecule targeted inhibitors. Whereas our study of published phase I trials continued to show a low response rate consistent with earlier studies, the relationship between response and dose does not always peak at 81% to 120% of RP2D anymore, likely due to the use of novel immunotherapy and targeted agents with distinct efficacy and toxicity patterns.

BRAINSTORM: A Multi-Institutional Phase 1/2 Study of RRx-001 in Combination With Whole Brain Radiation Therapy for Patients With Brain Metastases

To determine the recommended phase 2 dose of RRx-001, a radiosensitizer with vascular normalizing properties, when used with whole-brain radiation therapy (WBRT) for brain metastases and to assess whether quantitative changes in perfusion magnetic resonance imaging (MRI) after RRx-001 correlate with response. Five centers participated in this phase 1/2 trial of RRx-001 given once pre-WBRT and then twice weekly during WBRT. Four dose levels were planned (5 mg/m2, 8.4 mg/m2, 16.5 mg/m2, 27.5 mg/m2). Dose escalation was managed by the time-to-event continual reassessment method algorithm. Linear mixed models were used to correlate change in 24-hour T1, Ktrans (capillary permeability), and fractional plasma volume with change in tumor volume. Between 2015 and 2017, 31 patients were enrolled. Two patients dropped out before any therapy. Median age was 60 years (range, 30-76), and 12 were male. The most common tumor types were melanoma (59%) and non-small cell lung cancer (18%). No dose limiting toxicities were observed. The most common severe adverse event was grade 3 asthenia (6.9%, 2 of 29). The median intracranial response rate was 46% (95% confidence interval, 24-68) and median overall survival was 5.2 months (95% confidence interval, 4.5-9.4). No neurologic deaths occurred. Among 10 patients undergoing dynamic contrast-enhanced MRI, a reduction in Vp 24 hours after RRx-001 was associated with reduced tumor volume at 1 and 4 months (P ≤ .01). The addition of RRx-001 to WBRT is well tolerated with favorable intracranial response rates. Because activity was observed across all dose levels, the recommended phase 2 dose is 10 mg twice weekly. A reduction in fractional plasma volume on dynamic contrast-enhanced MRI 24 hours after RRx-001 suggests antiangiogenic activity associated with longer-term tumor response.

Comparative Efficacy of Bortezomib, Melphalan, and Prednisone (VMP) With or Without Daratumumab Versus VMP Alone in the Treatment of Newly Diagnosed Multiple Myeloma: Propensity Score Matching of ALCYONE and VISTA Phase III Studies

IntroductionBortezomib, melphalan, and prednisone (VMP) is the standard of care for transplant-ineligible newly diagnosed multiple myeloma. The phase III VISTA trial established the bortezomib dosing schedule for VMP. To mitigate bortezomib-associated toxicity, the phase III ALCYONE study of daratumumab plus VMP (D-VMP) versus VMP used modified bortezomib dosing. D-VMP demonstrated improved progression-free survival and overall response rate. Propensity score matching enables indirect comparisons by controlling for differences in baseline covariates. Patients and MethodsThe efficacy and safety of both arms of ALCYONE were compared with VISTA VMP using propensity score matching. ALCYONE D-VMP and VMP patients were matched on selected baseline characteristics to VISTA VMP patients, reducing or eliminating systematic differences between treatment groups. ResultsAfter matching, median progression-free survival and overall response rate were comparable for ALCYONE VMP and VISTA VMP, and were significantly improved with ALCYONE D-VMP versus VISTA VMP. Rates of grade 3/4 peripheral sensory neuropathy were significantly lower for both arms of ALCYONE versus VISTA VMP, with or without matching. ConclusionThis propensity score matching analysis demonstrates significant improvements in efficacy with ALCYONE D-VMP versus VISTA VMP and a significantly lower incidence of peripheral sensory neuropathy in both arms of ALCYONE versus VISTA VMP, although safety improvements may be due to different bortezomib administration routes (ALCYONE, subcutaneous; VISTA, intravenous).

Wide Variation in Perioperative Care in Anatomical Lung Resections in the Netherlands: A National Survey

This study aimed to describe perioperative care after anatomical lung resection in the Netherlands, before publication of Enhanced Recovery After Surgery/European Society of Thoracic Surgeons (ERAS/ESTS) guidelines in 2019. An online survey was sent to all 43 Dutch lung surgical centers in December 2017, addressing topics in the 4 phases of perioperative care (preoperative, admission, perioperative, postoperative). Respondents were requested to report care that would be delivered to a standardized patient without perioperative complications. To compare current care with ERAS/ESTS guidelines, we assigned an ERAS/ESTS score per hospital, weighted for evidence level per recommendation. Higher scores indicate higher application of recommendations. Response rate of centers was 100%, median response rate per question was 98% (interquartile range 94-100). Some perioperative recommendations are commonly applied (>85%), such as minimally invasive surgery and regional anesthesia; others, such as admission carbohydrate drinks, are not (<35%). Wide variation was observed regarding patient counselling, pre- and postoperative admission logistics, anemia correction, fluid management, pain management, and chest drain management. Median 62% (interquartile range 53%-72%) of the maximum ERAS/ESTS score was achieved. Large variation in ERAS/ESTS score between hospitals were found in all phases (preoperative: 6.0 [6.5-10.5] points, admission: 5.0 [1.0-6.0] points, perioperative: 21.5.0 [16.0-22.5] points, postoperative: 8.0 [5.0-8.5] points). Large variation exists in perioperative care after anatomical lung resection in the Netherlands. Given previously published data linking variation in perioperative care to variation in outcomes, standardization of perioperative care in lung surgery, preferably based on the ERAS/ESTS guidelines, may be warranted but requires further study.

Second-line treatment in patients with advanced extra-pulmonary poorly differentiated neuroendocrine carcinoma: a systematic review and meta-analysis.

Background:There is no standard second-line treatment for patients with advanced extra-pulmonary poorly differentiated neuroendocrine carcinoma (EP-PD-NEC). This study explored data evaluating second-line treatment in these patients.Methods:A search of MEDLINE and EMBASE identified studies reporting survival and/or response data for patients with EP-PD-NEC receiving second-line therapy. Association between various factors (age, gender, ECOG performance status, primary tumour location, morphology, Ki-67, treatment and grade 3/4 haematological toxicity) and response rate (RR), progression-free (PFS) and overall survival (OS) were assessed with a mixed effects meta-regression weighted by individual study sample size. Due to a small sample size, associations were reported quantitatively, based on magnitude of beta coefficient rather than statistical significance.Results:Of 83 identified studies, 19 were eligible, including 4 prospective and 15 retrospective studies. Analysis comprised 582 patients, with a median number of 19 patients in each study (range 5–100). Median age was 59 years (range 53–66). Median RR was 18% (range 0–50; 0% for single-agent everolimus, temozolomide, topotecan; 50% with amrubicin), median PFS was 2.5 months (range 1.15–6.0) and median OS was 7.64 months (range 3.2–22.0). Studies with a higher proportion of patients with a Ki-67>55% had lower RR (β = –0.73) and shorter OS (β = –0.82).Conclusion:Second-line therapy for patients with advanced EP-PD-NEC has limited efficacy and the variety of regimens used is diverse. Ki-67>55% is associated with worse outcomes. Prospective randomised studies are warranted to enable exploration of new treatment strategies.

Practices, Perceptions, and Attitudes in the Evaluation of Critically Ill Children for Bacteremia: A National Survey.

Sending blood cultures in children at low risk of bacteremia can contribute to a cascade of unnecessary antibiotic exposure, adverse effects, and increased costs. We aimed to describe practice variation, clinician beliefs, and attitudes about blood culture testing in critically ill children. Cross-sectional electronic survey. Fifteen PICUs enrolled in the Blood Culture Improvement Guidelines and Diagnostic Stewardship for Antibiotic Reduction in Critically Ill Children collaborative, an investigation of blood culture use in critically ill children in the United States. PICU clinicians (bedside nurses, resident physicians, fellow physicians, nurse practitioners, physician assistants, and attending physicians). None. Survey items explored typical blood culture practices, attitudes and beliefs about cultures, and potential barriers to changing culture use in a PICU setting. Fifteen of 15 sites participated, with 347 total responses, 15-45 responses per site, and an overall median response rate of 57%. We summarized median proportions and interquartile ranges of respondents who reported certain practices or beliefs: 86% (73-91%) report that cultures are ordered reflexively; 71% (61-77%) do not examine patients before ordering cultures; 90% (86-94%) obtain cultures for any new fever in PICU patients; 33% (19-61%) do not obtain peripheral cultures when an indwelling catheter is in place; and 64% (36-81%) sample multiple (vs single) lumens of central venous catheters for new fever. When asked about barriers to reducing unnecessary cultures, 80% (73-90%) noted fear of missing sepsis. Certain practices (culture source and indication) varied by clinician type. Obtaining surveillance cultures and routinely culturing all possible sources (each lumen of indwelling catheters and peripheral specimens) are positively correlated with baseline blood culture rates. There is variation in blood culture practices in the PICU. Fear and reflexive habits are common drivers of cultures. These practices may contribute to over-testing for bacteremia. Further investigation of how to optimize blood culture use is warranted.