Subsequent Randomized Studies Research Articles

Gösta Jönsson (1909-1978): A pioneer in the hormonal treatment of prostate cancer in Sweden.

Treatment of castration-resistant prostate cancer is and has been a challenge. In 1957, the chemist Imre Könyves came to Sweden as a refugee from Hungary and started to work at AB Leo, a pharmaceutical company in Helsingborg. In 1961, he started to synthesize compounds where the oestrogens were linked to a mustard group by a carbamate. This resulted in estramustine phosphate, which was initially tested against mammary cancer with disappointing results. He then started a cooperation with urology professor Gösta Jönsson, Head of the Department of Urology at the Lund University Hospital, to test estramustine phosphate against prostate cancer. Jönsson started clinical estramustine phosphate tests in 1966. His studies were one-armed and consecutive, with a "favourable response" in 83% of previously untreated patients. These favourable results could not be reproduced in later randomized controlled studies suggesting that estramustine phosphate as primary treatment was not better than conventional estrogenic treatment. Conclusions: Even if the results of Gösta Jönsson's studies could not be confirmed, the subsequent randomized studies of estramustine phosphate may hide the desired action of estramustine phosphate in a subgroup of patients. It has still not been elucidated whether estramustine phosphate has effects in this subgroup of patients with ostrogen-resistant prostate cancer.

CAN SERUM CONSENTRATION MEASUREMENTS OF ANTIHYPERTENSIVE DRUGS IMPROVE BLOOD PRESSURE CONTROL? A MULTICENTER DOUBLE BLINDED RANDOMIZED CONTROLLED TRIAL

Objective: Drug concentration in urine or serum using liquid chromatography coupled to mass-spectrometry (UHPLC-MS/MS) may disclose non-adherence. Whether this direct method will improve adherence is still unknown. In this multicenter randomized controlled trial with a double-blinded approach, we aimed to investigate if measurements and standardized information about serum concentrations of antihypertensive drugs (therapeutic drug monitoring (TDM)), could improve blood pressure (BP) control in documented non-adherent hypertensive patients. Design and method: Patients were > = 18 years old with eGFR >30 mL/min/1.73m2, prescribed > = 2 antihypertensive agents and on a stable treatment regimen for at least 4 weeks. Experienced pharmacologists assessed adherence status based on serum drug concentrations, dose and patient-reported time since last intake of the drugs. Patients received no information regarding use of blood samples to screen for non-adherence. The ethics committee approved the study. All patients signed written informed consent. Non-adherent patients with a systolic daytime ambulatory BP (ABPM) > = 135 mmHg were randomized 1:1 to TDM-intervention or not. The number of visits during 6 months follow-up were equal in both groups and antihypertensive medication regimens remained unchanged. Standardized TDM-information was given to the intervention-group at baseline and after 1 and 3 months. The control group remained uninformed about serum drug measurements until after completion of the study. Life style advice and information on necessity of BP treatment, how to remember to take medications and potential hypertension mediated end-organ damage were given to both groups. Investigators and patients were masked for BPs, and separate personnel measuring BPs were blinded to randomization group. Results: From 2017 to 2022, 606 patients (52.3%) of 1159 patients investigated had uncontrolled HT. The non-adherent patients were younger (57.8 vs 64.0 years, p < 0.001), duration of hypertension was shorter (12 vs 16 years, p = 0.024) and daytime diastolic ABPM (90 vs 84 mmHg, p < 0.001) and heart rate (76 vs 70 bpm, p < 0.001) were higher. Uncontrolled and non-adherent patients were enrolled into the subsequent randomized study performed with a double-blinded approach. Conclusions: There was no difference in the primary end-point, daytime systolic ABPM at 3 months, between TDM and control group (-6.7 vs -7.3 mmHg, p = 0.897).

176 DiscoverU: A feasibility study of an afterschool mentoring program for adolescents that integrates social emotional learning, physical activity, and mindful eating

OBJECTIVES/GOALS: Rising rates of youth obesity, diabetes, depression, and anxiety necessitate programs that address physical and mental health concurrently. We describe a feasibility study for DiscoverU, an afterschool mentoring program that integrates multiple aspects of health including social emotional learning, physical activity, and mindful eating. METHODS/STUDY POPULATION: Trained college students mentored middle and high school students in a Midwestern school district. DiscoverU was delivered 2 hours, 2 days/week for 8 weeks. Based on self-determination theory, DiscoverU was designed to meet National Afterschool Association healthy eating and physical activity and social emotional learning standards. We assessed feasibility with participant attendance (middle, high school, and college students) and acceptability through qualitative data from participants and relevant stakeholders regarding facilitators/barriers to program implementation. We observed indicators of mentoring, lesson fidelity, and assessed physical activity using accelerometry. Pre-post surveys measured self-realization, self-regulation, mindful eating, and physical activity self-efficacy. RESULTS/ANTICIPATED RESULTS: We expect DiscoverU to be feasible and well accepted. We anticipate attendance will be similar or higher than that of other afterschool programs in the district. From focus groups we expect to hear a variety of factors that facilitate/prevent program engagement and learn about the acceptability of specific lessons. We expect to gain insight on processes and procedures from school stakeholders that will inform the sustainability of DiscoverU. We expect program fidelity to be high and mentoring skills to improve over the course of the program. We anticipate the majority of participants will meet National Afterschool Alliance physical activity guidelines. Preliminary outcomes of self-determination, self-regulation, mindful eating, and physical activity self-efficacy are expected to improve over the program. DISCUSSION/SIGNIFICANCE: Findings will help determine the readiness of DiscoverU to be scaled to other schools. A subsequent randomized effectiveness study will evaluate DiscoverU’s impact on intervention mechanisms (e.g., self-determination, self-efficacy) as well as on physical activity, diet, weight, and depression/anxiety symptomology.

Immunotherapy and Hepatocellular Cancer: Where Are We Now?

Simple SummaryHCC is the third-leading cause of cancer death worldwide. Prior to the immunotherapy era, treatment of advanced HCC was dominated by antiangiogenic tyrosine kinase inhibitors, with a quite poor prognosis with a median survival time of around one year. In this review, we aimed to elaborate on all the advances in immunotherapy in HCC from the indisputable first-line therapy atezolizumab–bevacizumab in advanced HCC to promising new strategies. We highlight the new standard of care in advanced HCC, namely, the combination of immune checkpoint inhibitors (ICI) durvalumab–tremelimumab, and also discuss the different combinations of antiangiogenic drugs with ICI. We develop how the combination of ICI with locoregional therapies could become a future treatment in early and intermediate-stage HCC, and, finally, we outline several new cell-therapy-based strategies to follow in the coming years.Immunotherapy has demonstrated its effectiveness in many cancers. In hepatocellular carcinoma (HCC), promising results shown in the first phase II studies evaluating anti-PD-1 or anti-PD-L1 monotherapies resulted in their approval in the United States. Approval was not obtained in Europe; subsequent randomized studies in first- or second-line treatment did not confirm these initial results. However, first data with immunotherapy plus antiangiogenic treatments or dual immunotherapy combinations were positive. In this context, the combination of bevacizumab and atezolizumab took the lead. The IMbrave150 trial revealed an improved objective response rate (ORR), progression-free survival, and overall survival with this combination versus the previous standard, sorafenib. Subsequent results of dual immunotherapy with the anti-CTLA-4 and anti-PD-1 monotherapies tremelimumab and durvalumab (also superior to sorafenib monotherapy) confirmed the value of using a combination in first-line treatment. These significant therapeutic advances, and the increase in ORR, raise two main questions. Whereas response was very limited with previous treatments, the ORR reported with these new combinations are between 20% and 30%. This raises the question of whether immunotherapy (ICI single agent, combination of ICI with antiangiogenic agent or other antitumoral treatment) can be used in patients beyond those in BCLC group C, the traditional candidate group for systemic therapy. We have thus seen an increasing number of patients previously treated with trans-arterial chemoembolization (BCLC group B) receiving these new treatments, and we develop the results of several studies combining loco-regional therapies and immunotherapy-based systemic treatments. The other major question is that of how and when to use these medical treatments as “adjuvants” to interventional radiology or surgery; the results of several works are discussed for this purpose. In this review, we cover all of these points in a fairly comprehensive manner.

Shared meditation involving cancer patients, health professionals and third persons is relevant and improves well-being: IMPLIC pilot study

BackgroundAlleviating suffering and improving quality of life are universally shared goals. In this context, we implemented a pilot study to assess the feasibility and acceptability of a mindfulness intervention in the form of meditation involving together cancer patients, health professionals, and third persons.MethodsTwo groups of 15 participants equally composed of patients, health professionals and third persons were constituted. A dedicated programme on mindfulness and compassion was constructed, including 12 weekly sessions of 1.5 h and a half-day retreat. Adherence and satisfaction with the programme were evaluated. All participants completed questionnaires on perceived stress, quality of life, mindfulness, empathy, and self-efficacy. Burnout was assessed in health professionals.ResultsShared meditation was feasible as 70% of participants attended ≥ 80% of the 13 meditation sessions. Satisfaction with the programme was high (median satisfaction score: 9.1 out of 10) and all participants expressed positive attitudes towards shared meditation and a benefit on their global quality of life. Participants reported significant improvement in stress (p < 0.001), global quality of life (p = 0.004), self-efficacy (p < 0.001), and mindfulness skills (p < 0.001) from baseline to post-programme.ConclusionsThis study demonstrated the feasibility of a shared dedicated meditation programme in terms of participation and acceptability of participants. The measured benefits observed among participants furthermore justify the interest of a subsequent randomized study aiming to demonstrate the potential added value of shared meditation by promoting bridge-building between cancer patients, health professionals and others.Trial RegistrationClinicalTrials.gov. NCT04410185. Registered on June 1, 2020.

119 Recruiting rural clinics to participate in an HPV vaccination intervention: protocol for a feasibility study and subsequent effectiveness trial

OBJECTIVES/GOALS: Rural teens have lower human papillomavirus (HPV) vaccination rates than urban teens, promoting geographical cervical cancer disparities. Giving HPV vaccination earlier than the recommended 11-12 years might increase vaccination rates. We describe a feasibility study for recruiting rural clinics to participate in early HPV vaccination studies. METHODS/STUDY POPULATION: Leveraging professional contacts, we identified two clinics in North Carolina that serve predominantly rural populations. To assess the feasibility of adapting clinic monitoring systems to promote early vaccination, we requested to review electronic medical records (EMR) to identify the size of the vaccine-eligible patient population, HPV vaccination coverage, and the accuracy of EMR queries to monitor HPV vaccination status. Next, we completed in-depth interviews with clinic staff to collect insights on perceived advantages and disadvantages of promoting early HPV vaccination at 9-10 years, and potential facilitators and barriers to doing so. RESULTS/ANTICIPATED RESULTS: We expect that existing clinic systems will easily accommodate early recommendation and administration of HPV vaccine by expanding EMR queries and vaccination status indicators to include 9- and 10-year-olds. Clinics that are interested in promoting early HPV vaccination can use these adapted tools to monitor vaccine coverage over time. From in-depth interviews we expect to encounter a mix of support and hesitation to promote early HPV vaccination, based on personal beliefs on safety and effectiveness of HPV vaccination, perceptions of adolescent HPV risk, perceptions of parental acceptability of HPV vaccination, and perceived burden of changing current clinic protocols. DISCUSSION/SIGNIFICANCE: This feasibility study’s findings will help determine clinic readiness to recommend early HPV vaccination, and intervention components that maximize staff acceptability of early HPV vaccination. A subsequent randomized effectiveness study will evaluate early HPV vaccination as a method to increase rural adolescent vaccination coverage.

A Trial Protocol to Investigate the Incidence of Postoperative Bowel Obstruction after Laparoscopic Colorectal Cancer Surgery Using an Absorbable Adhesion Barrier Material (INTERCEEDⓇ) (Balsam CEED Study): A Prospective, Multicenter, Observational Study.

Background: Some studies have reported that adhesion prevention barriers (APBs) reduce adhesion after abdominal surgery; however, evidence showing that APBs reduce the incidence of postoperative small bowel obstruction (SBO), one of the most serious complications after abdominal surgery, is little. One concern is that APBs are usually applied only under the midline incision, although adhesion can occur at any place in the peritoneum where an incision is made during surgery. INTERCEEDⓇ is an APB that reportedly prevents postoperative SBO after surgery. This study aims to assess the clinical utility of INTERCEEDⓇ for the prevention of SBO after laparoscopic colorectal cancer surgery and determine whether the application site of INTERCEEDⓇ affects the incidence of SBO. Methods/Design: This study is a prospective, multicenter, observational study conducted in Japan. The primary end point is the incidence of postoperative SBO 2 years after laparoscopic colorectal cancer surgery. The secondary end points include whether the site of the application of INTERCEEDⓇ affects the incidence of SBO. Each surgeon selects one of the following three procedures: 1) INTERCEEDⓇ is placed only under the midline incision; 2) INTERCEEDⓇ is placed at the site of bowel mobilization and/or lymph node dissection, but not under the midline incision; and 3) INTERCEEDⓇ is placed at both sites. Discussion: This is the first study to assess whether the placement of APBs affects the incidence of SBO. The study results may lead to a subsequent randomized study.

Drug Transporter ABCB1 SNP Predicts Outcome in Patients with Acute Myeloid Leukemia Treated with Gemtuzumab Ozagamicin: A Report from Children's Oncology Group AAML0531 Trial

Background: Gemtuzumab Ozogamicin (GO), is first ever approved immunotherapy for relapsed AML patients. GO is a humanized anti-CD33 antibody linked with the toxin calicheamicin gamma. Calicheamicin induces DNA damage and cell death once the linked CD33 antibody facilitates its uptake. Previous studies have shown that the drug efflux transporter PgP1, which is encoded by gene ABCB1, influences the cellular accumulation of calicheamicin. PgP1 activity in leukemic cells is also inversely correlated with GO response in patients with AML. Although GO was withdrawn from market due to lack of benefit and increase in early mortality observed in SWOG-S0106 study subsequent multiple randomized studies have shown benefit of GO with significant improvement observed in patients with favorable cytogenetic risk features. In light of these results and recent favorable voting by FDA oncology drug advisory committee based on results of ALFA-0701 trail demonstrating a favorable risk:benefit profile for GO there is increased enthusiasm among AML investigators. Given the potential comeback of GO, it is very timely to focus efforts on identifying genetic biomarkers that can improve our ability to develop personalized treatment with GO. In this study evaluate whether single nucleotide polymorphisms (SNPs) in ABCB1 gene are predictive of GO response in patients with AML.Method: Genomic DNA samples from 942 patients enrolled in the COG trial AAML0531 who gave consent for the study were genotyped for 12 SNPs in the ABCB1 gene . Since AAML0531 was designed to test the benefit of GO in a randomized manner, we analyzed the effect of ABCB1 genotypes on outcomes and risk of relapse (RR) between patients treated with or without addition of GO (GO vs. No-GO respectively).Results: The ABCB1 SNP C3435T (rs1045642) was significantly associated with outcome when analyzed by GO vs. No-GO arm. Presence of C3435T change has been previously associated with lower PgP1 expression. For AML patients in the GO arm, presence of variant allele (CT and TT genotype) was significantly associated with lower risk of relapse (RR) from the end of course 1 (GO vs. No-GO arm: RR: 30 ± 6%, n = 259 vs. 46 ± 7%, n= 235; P < 0.0001) and better 5-year event free survival (EFS) from study than for those in the No-GO arm (GO vs. No-GO arm: 55 ± 6%, n = 340 vs. 45 ± 5%, n= 337; P= 0.006). However, patients with the CC genotype showed no differences in RR (GO and No-GO arms: 45 ± 10%, n = 97 vs. 40 ± 11%, n= 91; P= 0.514) and EFS (GO and No-GO arms: 44 ± 9%, n = 128 vs. 50 ± 9%, n= 132; P= 0.425) between the GO and No-GO arms (Fig 1). Further the rs1045642 genotype was significantly associated with EFS (CC vs. CT/TT: 44 ± 9% vs. 55 ± 6%; P=0.022) and RR (CC vs. CT/TT 45 ± 10% vs. 30 ± 6%, P=0.007) for patients in the GO arm but for those in the No-GO arm no difference in outcome between the genotypes was observed (RR: P=0.278; EFS P=0.466).Conclusion: Our results show that for the nonsynonymous SNP rs1045642 (C>T) in an drug efflux transporter ABCB1, the presence of T allele is associated with better response in patients treated with GO based as compared to standard arm. Since ABCB1 is involved in efflux of calicheamicin the presence of a low expression T allele might result in higher intracellular accumulation of calicheamicin and thus better response in patients treated with GO. [Display omitted] DisclosuresLoken:Hematologics Inc: Employment, Equity Ownership. Walter:ADC Therapeutics: Research Funding; Aptevo Therapeutics: Research Funding.

Effectiveness of online education for recruitment to an Alzheimer's disease prevention clinical trial.

IntroductionLow awareness of Alzheimer's disease (AD) clinical trials is a recruitment barrier. To assess whether online education may affect screening rates for AD prevention clinical trials, we conducted an initial prospective cohort study (n = 10,450) and subsequent randomized study (n = 351) using an online digital tool: AlzU.org.MethodsA total of 10,450 participants were enrolled in an initial cohort study and asked to complete a six‐lesson course on AlzU.org, as well as a baseline and 6‐month follow‐up questionnaire. Participants were stratified into three groups based on lesson completion at 6 months: group 1 (zero to one lesson completed), group 2 (two to four lessons), and group 3 (five or more lessons). For the subsequent randomized‐controlled trial (RCT), 351 new participants were enrolled in a six‐lesson course (n = 180) versus a time‐neutral control (n = 171). Screening and enrollment in the Anti‐Amyloid Treatment in Asymptomatic AD (A4) clinical trial were reported via the 6‐month questionnaire and are the primary outcomes.Results Cohort: 3.9% of group 1, 5% of group 2, and 8.4% of group 3 screened for the A4 trial. Significant differences were found among the groups (P < 0.001). Post hoc analyses showed differences in A4 screening rates between groups 1 and 3 (P < 0.001) and groups 2 and 3 (P = 0.0194). There were no differences in enrollment among the three groups. RCT: 2.78% of the intervention group screened for A4 compared to 0% of controls (P = 0.0611).DiscussionOnline education via the AlzU.org digital tool may serve as an effective strategy to supplement clinical trial recruitment.

Sepsis: Early Recognition and Optimized Treatment.

Sepsis is a life-threatening condition caused by infection and represents a substantial global health burden. Recent epidemiological studies showed that sepsis mortality rates have decreased, but that the incidence has continued to increase. Although a mortality benefit from early-goal directed therapy (EGDT) in patients with severe sepsis or septic shock was reported in 2001, three subsequent multicenter randomized studies showed no benefits of EGDT versus usual care. Nonetheless, the early administration of antibiotics and intravenous fluids is considered crucial for the treatment of sepsis. In 2016, new sepsis definitions (Sepsis-3) were issued, in which organ failure was emphasized and use of the terms “systemic inflammatory response syndrome” and “severe sepsis” was discouraged. However, early detection of sepsis with timely, appropriate interventions increases the likelihood of survival for patients with sepsis. Also, performance improvement programs have been associated with a significant increase in compliance with the sepsis bundles and a reduction in mortality. To improve sepsis management and reduce its burden, in 2017, the World Health Assembly and World Health Organization adopted a resolution that urged governments and healthcare workers to implement appropriate measures to address sepsis. Sepsis should be considered a medical emergency, and increasing the level of awareness of sepsis is essential.

A Phase II Clinical Trial of Azacitidine and Vorinostat for Patients with Acute Myeloid Leukemia (AML) or Myelodysplastic Syndromes (MDS) with Poor Performance Status, Comorbidities, Other Active Malignancies or Organ Dysfunction Not Eligible for Conventional Clinical Trials

A Phase II Clinical Trial of Azacitidine and Vorinostat for Patients with Acute Myeloid Leukemia (AML) or Myelodysplastic Syndromes (MDS) with Poor Performance Status, Comorbidities, Other Active Malignancies or Organ Dysfunction Not Eligible for Conventional Clinical Trials

Non-invasive ventilation in immunocompromised patients with acute hypoxemic respiratory failure.

The survival rate of immunocompromised patients has improved over the past decades in light of remarkable progress in diagnostic and therapeutic options. Simultaneously, there has been an increase in the number of immunocompromised patients with life threatening complications requiring intensive care unit (ICU) treatment. ICU admission is necessary in up to 15% of patients with acute leukemia and 20% of bone marrow transplantation recipients, and the main reason for ICU referral in this patient population is acute hypoxemic respiratory failure, which is associated with a high mortality rate, particularly in patients requiring endotracheal intubation. The application of non-invasive ventilation (NIV), and thus the avoidance of endotracheal intubation and invasive mechanical ventilation with its side effects, appears therefore of great importance in this patient population. Early trials supported the benefits of NIV in these settings, and the 2011 Canadian guidelines for the use of NIV in critical care settings suggest the use of NIV in immune-compromised patients with a grade 2B recommendation. However, the very encouraging results from initial seminal trials were not confirmed in subsequent observational and randomized clinical studies, questioning the beneficial effect of NIV in immune-compromised patients. Based on these observations, a French group led by Azoulay decided to assess whether early intermittent respiratory support with NIV had a role in reducing the mortality rate of immune-compromised patients with non-hypercapnic hypoxemic respiratory failure developed in less than 72 h, and hence conducted a multicenter randomized controlled trial (RCT) in experienced ICUs in France. This perspective reviews the findings from their RCT in the context of the current critical care landscape, and in light of recent results from other trials focused on the early management of acute hypoxemic respiratory failure.

Renal sympathetic denervation after Symplicity HTN-3 and therapeutic drug monitoring in severe hypertension.

Renal sympathetic denervation (RDN) has been and is still proposed as a new treatment modality in patients with apparently treatment resistant hypertension (TRH), a condition defined as persistent blood pressure elevation despite prescription of at least 3 antihypertensive drugs including a diuretic. However, the large fall in blood pressure after RDN reported in the first randomized study, Symplicity HTN-2 and multiple observational studies has not been confirmed in five subsequent prospective randomized studies and may be largely explained by non-specific effects such as improvement of drug adherence in initially poorly adherent patients (the Hawthorne effect), placebo effect and regression to the mean. The overall blood-pressure lowering effect of RDN seems rather limited and the characteristics of true responders are largely unknown. Accordingly, RDN is not ready for clinical practice. In most patients with apparently TRH, drug monitoring and improvement of drug adherence may prove more effective and cost-beneficial to achieve blood pressure control. In the meantime, research should aim at identifying characteristics of those patients with truly TRH who may respond to RDN.

Glycemic Targets for the Critically Ill Patient

Critically ill patients often experience hyperglycemia, which may be associated with increased morbidity and mortality. In 2001, van den Berghe et al. suggested significant benefit of normalization of blood glucose level in critically ill patients using intensive intravenous insulin therapy. Subsequent multicenter randomized studies, however, demonstrated adverse effects of tight glucose control. Therefore, while the need for glucose control in critically ill patients is generally accepted, the treatment thresholds for initiation of insulin therapy or target glucose values are still undetermined. Furthermore, occurrence of a hypoglycemic event during intensive insulin therapy is known to be an independent predictor of clinical outcome, and glycemic variability is an important variable of glucose management in the critically ill patients. Novel technological approaches such as a continuous glucose monitoring system (CGMS) might help to overcome some problems of tight glucose control by reducing the risk of hypoglycemia and minimizing glycemic variability.

Renal sympathetic denervation after Symplicity HTN-3 and therapeutic drug monitoring in patients with resistant hypertension to improve patients' adherence.

Renal sympathetic denervation (RDN) has been proposed as a new treatment modality in patients with apparent treatment-resistant hypertension (TRH), a condition defined as persistent blood pressure (BP) elevation despite prescription of at least three anti-hypertensive drugs including a diuretic. However, the large fall in BP reported after RDN in Symplicity HTN-2, the first randomized study, and in multiple observational studies has not been confirmed in five subsequent prospective randomized studies. The reduction in BP may be mostly due to non-specific effects, such as improvement of drug adherence in initially poorly adherent patients (the Hawthorne effect), placebo effect and regression to the mean. The overall BP lowering effect of RDN seems rather limited and the characteristics of the true responders remain largely unknown. Accordingly, RDN is not ready for clinical practice. In most patients with TRH, drug monitoring and subsequent improvement of drug adherence may prove more effective and cost-effective to achieve BP control. In the meantime, research should aim at identifying characteristics of those few patients adherent to drug treatment who has TRH and may respond to RDN.

Phase 2 clinical trial of rapamycin-resistant donor CD4+ Th2/Th1 (T-Rapa) cells after low-intensity allogeneic hematopoietic cell transplantation

AbstractIn experimental models, ex vivo induced T-cell rapamycin resistance occurred independent of T helper 1 (Th1)/T helper 2 (Th2) differentiation and yielded allogeneic CD4+ T cells of increased in vivo efficacy that facilitated engraftment and permitted graft-versus-tumor effects while minimizing graft-versus-host disease (GVHD). To translate these findings, we performed a phase 2 multicenter clinical trial of rapamycin-resistant donor CD4+ Th2/Th1 (T-Rapa) cells after allogeneic-matched sibling donor hematopoietic cell transplantation (HCT) for therapy of refractory hematologic malignancy. T-Rapa cell products, which expressed a balanced Th2/Th1 phenotype, were administered as a preemptive donor lymphocyte infusion at day 14 post-HCT. After T-Rapa cell infusion, mixed donor/host chimerism rapidly converted, and there was preferential immune reconstitution with donor CD4+ Th2 and Th1 cells relative to regulatory T cells and CD8+ T cells. The cumulative incidence probability of acute GVHD was 20% and 40% at days 100 and 180 post-HCT, respectively. There was no transplant-related mortality. Eighteen of 40 patients (45%) remain in sustained complete remission (range of follow-up: 42-84 months). These results demonstrate the safety of this low-intensity transplant approach and the feasibility of subsequent randomized studies to compare T-Rapa cell-based therapy with standard transplantation regimens. This trial was registered at www.cancer.gov/clinicaltrials as #NCT 00077480.

Response to Letters Regarding Article, “Platelet Reactivity and Cardiovascular Outcomes After Percutaneous Coronary Intervention: A Time-Dependent Analysis of the Gauging Responsiveness With a VerifyNow P2Y12 Assay: Impact on Thrombosis and Safety (GRAVITAS) Trial”

We thank Dr Nezami and colleagues for their interest in our study. As they note, statin therapy has been associated with improved clinical outcomes after percutaneous coronary intervention. Although an early observational study suggested an interaction between atorvastatin and the antiplatelet effect of clopidogrel in the acute phase of treatment, presumably due to shared metabolism via the CYP3A4 pathway, this does not occur during maintenance clopidogrel therapy and was not confirmed in subsequent randomized pharmacodynamic studies. In addition, clinical outcome studies have failed to identify a clear impact of statins on the ability of clopidogrel to reduce recurrent ischemic events.1 In order to address the questions of Dr Nezami and colleagues about our trial, we assessed the effect of statin use in GRAVITAS by incorporating this covariate into our time-dependent multivariate regression model.2 Statin use was not associated with clinical outcome at 60 days (adjusted hazard ratio [HR] 0.89, 95% confidence interval [CI], 0.27–3.02) or 6 months (adjusted HR 0.86. 95% CI, 0.39–1.91), nor did it affect the relationship between on-treatment reactivity <208 PRU and outcome at either time point (adjusted HR 0.23, 95% CI, 0.05–0.98, P =0.047 at 60 days and adjusted HR 0.54, 95% CI: 0.28–1.04, P …

Symptomatic reactions, clinical outcomes and patient satisfaction associated with upper cervical chiropractic care: A prospective, multicenter, cohort study

BackgroundObservational studies have previously shown that adverse events following manipulation to the neck and/or back are relatively common, although these reactions tend to be mild in intensity and self-limiting. However, no prospective study has examined the incidence of adverse reactions following spinal adjustments using upper cervical techniques, and the impact of this care on clinical outcomes.MethodsConsecutive new patients from the offices of 83 chiropractors were recruited for this practice-based study. Clinical outcome measures included 1) Neck pain disability index (100-point scale), 2) Oswestry back pain index (100-point scale), 3) 11-point numerical rating scale (NRS) for neck, headache, midback, and low back pain, 4) treatment satisfaction, and 5) Symptomatic Reactions (SR). Data were collected at baseline, and after approximately 2 weeks of care. A patient reaching sub-clinical status for pain and disability was defined as a follow-up score <3 NRS and <10%, respectively. A SR is defined as a new complaint not present at baseline or a worsening of the presenting complaint by >30% based on an 11-point numeric rating scale occurring <24 hours after any upper cervical procedure.ResultsA total of 1,090 patients completed the study having 4,920 (4.5 per patient) office visits requiring 2,653 (2.4 per patient) upper cervical adjustments over 17 days. Three hundred thirty- eight (31.0%) patients had SRs meeting the accepted definition. Intense SR (NRS ≥8) occurred in 56 patients (5.1%). Outcome assessments were significantly improved for neck pain and disability, headache, mid-back pain, as well as lower back pain and disability (p <0.001) following care with a high level (mean = 9.1/10) of patient satisfaction. The 83 chiropractors administered >5 million career upper cervical adjustments without a reported incidence of serious adverse event.ConclusionsUpper cervical chiropractic care may have a fairly common occurrence of mild intensity SRs short in duration (<24 hours), and rarely severe in intensity; however, outcome assessments were significantly improved with less than 3 weeks of care with a high level of patient satisfaction. Although our findings need to be confirmed in subsequent randomized studies for definitive risk-benefit assessment, the preliminary data shows that the benefits of upper cervical chiropractic care may outweigh the potential risks.

SB‐656933, a novel CXCR2 selective antagonist, inhibits ex vivo neutrophil activation and ozone‐induced airway inflammation in humans

Receptor antagonists that block the binding of chemokines such as CXCL8 (IL-8) are effective in animals models of neutrophil-mediated inflammation. It has been hypothesized that selective inhibition of neutrophil trafficking and activation may be a useful adjunct for the treatment of inflammatory airway diseases such as chronic obstructive pulmonary disease or cystic fibrosis. A CXCR1/2 receptor antagonist has shown activity in an ozone challenge model in humans. SB-656933, a selective CXCR2 antagonist, is safe and well-tolerated at single doses and is shown to inhibit agonist (CXCL1)-mediated expression of the CD11b on peripheral blood neutrophils as well as ozone-induced airway neutrophilia in healthy subjects. To determine the safety and tolerability of a novel selective CXCR2 antagonist and assess its pharmacodynamic effects using measures of neutrophil activation and function, including CD11b expression in whole blood and ozone-induced airway inflammation in healthy subjects. Flow cytometric determination of ex vivo CXCL1-induced CD11b expression on peripheral blood neutrophils was performed following single dose oral administration of SB-656933 (dose range 2-1100 mg). A subsequent randomized study (placebo, 50 mg and 150 mg) was performed to explore the dose-response for ozone-induced airway inflammation, as measured by sputum biomarkers. Oral administration of SB-656933 resulted in significant inhibition of CXCL1-induced CD11b expression on peripheral blood neutrophils at single doses greater than or equal to 50 mg. Maximum inhibition (70%) relative to placebo was observed following administration of SB-656933 400 mg (95% CI 60%, 77%). This was sustained up to a dose of 1100 mg. Single doses of SB-656933 reduced ozone-induced airway inflammation in a dose-dependent manner. Relative to placebo, there were 55% (95% CI 20%, 75%) and 74% (95% CI 55%, 85%) fewer neutrophils in the sputum of subjects after a single dose of 50 mg or 150 mg, respectively. There was a corresponding reduction in myeloperoxidase concentrations in the sputum supernatant of 32.8% (95% CI 9.2, 50.3) and 50.5% (95% CI 33.3, 63.3). SB-656933 was safe and well-tolerated at all doses. SB-656933 is a CXCR2 antagonist that demonstrates dose-dependent effects on neutrophil activation and recruitment within a well-tolerated dose range. These data suggest that SB-656933 may be an effective agent in neutrophil-predominant diseases.

Methylphenidate Transdermal System in Adults With Past Stimulant Misuse

Objective: This 8-week, open-label trial assessed the efficacy of methylphenidate transdermal system (MTS) in 14 adult individuals diagnosed with ADHD and with a history of stimulant misuse, abuse, or dependence. Method: The primary efficacy endpoint was the Wender-Reimherr Adult ADHD Scale (WRAADS), and secondary efficacy endpoints included the Clinical Global Impression (CGI) ratings and substance abuse as quantified by urine drug screens and self-reported use. Results: Significant improvements from baseline were found on both the WRAADS and CGI measurements. No abuse of the study medication was observed. Conclusion: The findings suggested that MTS may improve ADHD symptoms in adults with a history of stimulant misuse; however, there were limitations. The study data showed the need for subsequent randomized studies that further explore findings made in this study.