Engraftment syndrome (ES), characterized by fever, rash, pulmonary edema, weight gain, liver and renal dysfunction, and/or encephalopathy, occurs at the time of neutrophil recovery following hematopoietic cell transplantation (HCT). In this study, we evaluated the incidence, clinical features, risk factors, and outcomes of ES in children and adults undergoing first-time allogeneic HCT. Among 927 patients, 119 (13%) developed ES at a median of 10 days (interquartile range 9–12) post-HCT. ES patients experienced significantly higher cumulative incidence of grade 2–4 acute GVHD at day 100 (75% vs. 34%, p<0.001) and higher non-relapse mortality at 2 years (38% vs. 19%, p<0.001), compared with non-ES patients, resulting in lower overall survival at 2 years (38% vs. 54%, p<0.001). There was no significant difference in relapse at 2 years (26% vs. 31%, p=0.772). ST2, IL2Rα, and TNFR1 plasma biomarker levels were significantly elevated in ES patients. Our results illustrate the clinical significance and prognostic impact of ES on allogeneic HCT outcomes. Despite early recognition of the syndrome and prompt institution of corticosteroid therapy, outcomes in ES patients were uniformly poor. This study suggests the need for a prospective approach of collecting clinical features combined with correlative laboratory analyses to better characterize ES.

BACKGROUND Acute graft-versus-host disease (GVHD) remains a significant barrier to a more widespread application of allogeneic hematopoietic stem cell transplantation (HSCT). Vorinostat (suberoylanilide hydroxamic acid) is a histone deacetylases (HDAC) inhibitor that has been shown to attenuate GVHD in pre-clinical models. We aimed to study the safety and activity of vorinostat in combination with standard immunoprophylaxis for GVHD prevention in patients undergoing related donor reduced intensity conditioning HSCT. METHODS In this prospective, single-arm phase 1/2 study of vorinostat, we recruited patients with high-risk hematologic malignances at two centers in the USA. We enrolled patients aged 18 years or older who were candidates for a reduced intensity conditioning HSCT and had an available 8/8- or 7/8-Human Leukocyte Antigen (HLA) matched related donor. Disease status had to be adequately controlled at the time of transplant. All patients received a conditioning regimen consisting of fludarabine 40 mg/m2 daily for four days (total dose 160 mg/m2) and busulfan 3·2 mg/kg daily for two days (total dose 6·4 mg/kg). GVHD prophylaxis consisted of mycophenolate mofetil 1 gram three times daily from day 0 and through day 28 and tacrolimus beginning on day −3 pre-HSCT and tapered beginning on day 56 and discontinued by day 180 post-HSCT in the absence of GVHD. The investigational agent, vorinostat, was initiated on day −10 through day 100 post-HSCT. The primary endpoint of the study was grade 2–4 acute GVHD by day 100. We expected to reduce the incidence to 25% from 42% based on similarly treated patients from the study centers and published literature. Patients were assessed for both toxicity and the primary endpoint if at least 21 days of vorinostat were administered. Patients who received less than 21 days of therapy were still assessed for toxicity and were replaced in accordance to the protocol. The trial is registered with ClinicalTrials.gov, NCT00810602. FINDINGS Between March 2008 and February 2013, we enrolled 50 patients evaluable for both toxicity and response. All patients engrafted neutrophils and platelets at expected times post-HSCT. The median percentages of chimerism in whole-blood at day 100 and 1-year were 98% (interquartile range [IQR], 98–100) and 100% (IQR, 100–100), respectively. The primary endpoint of the study was met with a day 100 cumulative incidence of grade 2–4 acute GVHD of 22% (95% cumulative incidence: 13%, 36%). Eight additional patients enrolled were assessed for toxicity only, in accordance with the protocol, because they received less than 21 days of study drug. The most common non-hematologic adverse events were all grade 3 and included electrolyte disturbances (N=15), hyperglycemia (N=10), infections (N=4), mucositis (N=4), and elevated liver enzymes (N=3). There was one grade 4 hypokalemia event and two grade 4 infections. Non-symptomatic thrombocytopenia which occurred after engraftment was the most common hematologic grade 3 or 4 adverse event (N=9), but was transien...

• Plasma concentrations of CXCL9 are elevated at the onset of cGVHD diagnosis, but not in patients with cGVHD for more than 3 months.• Plasma concentrations of CXCL9 are impacted by immunosuppressive therapy.There are no validated biomarkers for chronic GVHD (cGVHD). We used a protein microarray and subsequent sequential enzyme-linked immunosorbent assay to compare 17 patients with treatment-refractory de novo-onset cGVHD and 18 time-matched control patients without acute or chronic GVHD to identify 5 candidate proteins that distinguished cGVHD from no cGVHD: CXCL9, IL2Ra, elafin, CD13, and BAFF. We then assessed the discriminatory value of each protein individually and in composite panels in a validation cohort (n 5 109). CXCL9 was found to have the highest discriminatory value with an area under the receiver operating characteristic curve of 0.83 (95% confidence interval, 0.74-0.91). CXCL9 plasma concentrations above the median were associated with a higher frequency of cGVHD even after adjustment for other factors related to developing cGVHD including age, diagnosis, donor source, and degree of HLA matching (71% vs 20%; P < .001). A separate validation cohort from a different transplant center (n 5 211) confirmed that CXCL9 plasma concentrations above the median were associated with more frequent newly diagnosed cGVHD after adjusting for the aforementioned factors (84% vs 60%; P 5 .001). Our results confirm that CXCL9 is elevated in patients with newly diagnosed cGVHD. (Blood. 2014;123(5):786-793)

A simple molecular method guiding sequential therapy can achieve a high eradication rate in the third-line treatment of refractory H. pylori infection.

Background Pediatric hematology-oncology (PHO) patients are at significant risk for developing central line-associated bloodstream infections (CLA-BSIs) due to their prolonged dependence on such catheters. Effective strategies to eliminate these preventable infections are urgently needed. In this study, we investigated the implementation of bundled central line maintenance practices and their effect on hospital-acquired CLA-BSIs. Materials and Methods CLA-BSI rates were analyzed within a single-institution’s PHO unit between January 2005 and June 2011. In May 2008, a multidisciplinary quality improvement team developed techniques to improve the PHO unit’s safety culture and implemented the use of catheter maintenance practices tailored to PHO patients. Data analysis was performed using time-series methods to evaluate the pre- and post-intervention effect of the practice changes. Results The pre-intervention CLA-BSI incidence was 2.92 per 1000-patient days (PD) and coagulase-negative Staphylococcus was the most prevalent pathogen (29%). In the post-intervention period, the CLA-BSI rate decreased substantially (45%) to 1.61 per 1000-PD (p<0.004). Early on, blood and marrow transplant (BMT) patients had a three-fold higher CLA-BSI rate compared to non-BMT patients (p<0.033). With additional infection control countermeasures added to the bundled practices, BMT patients experienced a larger CLA-BSI rate reduction such that BMT and non-BMT CLA-BSI rates were not significantly different post-intervention. Conclusions By adopting and effectively implementing uniform maintenance catheter care practices, learning multidisciplinary teamwork, and promoting a culture of patient safety, the CLA-BSI incidence in our study population was significantly reduced and maintained.

Cancer is a condition that has plagued humanity for thousands of years, with the first depictions dating back to ancient Egyptian times. However, not until recent decades have biological therapeutics been developed and refined enough to safely and effectively combat cancer. Three unique immunotherapies have gained traction in recent decades: adoptive T cell transfer, checkpoint inhibitors, and bivalent antibodies. Each has led to clinically approved therapies, as well as to therapies in preclinical and ongoing clinical trials. In this review, we outline the method by which these 3 immunotherapies function as well as any major immunotherapeutic drugs developed for treating a variety of cancers.

Tumor therapy with replication competent viruses is an exciting approach to cancer eradication where viruses are engineered to specifically infect, replicate, spread and kill tumor cells. The outcome of tumor virotherapy is complex due to the variable interactions between the cancer cell and virus populations as well as the immune response. Oncolytic viruses are highly efficient in killing tumor cells in vitro, especially in a 2D monolayer of tumor cells, their efficiency is significantly lower in a 3D environment, both in vitro and in vivo. This indicates that the spatial dimension may have a major influence on the dynamics of virus spread. We study the dynamic behavior of a spatially explicit computational model of tumor and virus interactions using a combination of in vitro 2D and 3D experimental studies to inform the models. We determine the number of nearest neighbor tumor cells in 2D (median = 6) and 3D tumor spheroids (median = 16) and how this influences virus spread and the outcome of therapy. The parameter range leading to tumor eradication is small and even harder to achieve in 3D. The lower efficiency in 3D exists despite the presence of many more adjacent cells in the 3D environment that results in a shorter time to reach equilibrium. The mean field mathematical models generally used to describe tumor virotherapy appear to provide an overoptimistic view of the outcomes of therapy. Three dimensional space provides a significant barrier to efficient and complete virus spread within tumors and needs to be explicitly taken into account for virus optimization to achieve the desired outcome of therapy.

Despite major improvements over the past several decades, many patients undergoing hematopoietic stem cell transplants (HSCT) continue to suffer from significant treatment-related morbidity and mortality. Clinical research studies (trials) have been integral to advancing the standard-of-care in HSCT. However, one of the biggest challenges with clinical trials is the low participation rate. While barriers to participation in cancer clinical trials have been previously explored, studies specific to HSCT are lacking. The current study was undertaken to examine the knowledge, attitudes, and perceptions of HSCT patients regarding clinical trials. Using focus groups, participants responded to open-ended questions that assessed factors influencing decision-making about HSCT clinical trials. Suggestions for improvements in the recruitment process were also solicited among participants. Seventeen adult HSCT patients and six parents of pediatric HSCT patients participated in the study. The median age was 56 years (range, 18-70) and 44 years (range, 28-54) for adult patients and parents, respectively. Participants universally indicated that too much information was provided within the informed consents and they were intimidated by the medical and legal language. Despite the large amount of information provided to them at the time of study enrollment, there was limited knowledge retention and recall of study details. Nevertheless, participants reported overall positive experiences with clinical trial participation and many would readily choose to participate again. A common concern among participants was the uncertainty of study outcome and general lack of feedback about results at the end of the study. Participants suggested that investigators provide more condensed and easier-to-understand informed consents and follow-up of study findings. These findings could be used to help guide the development of improved consent documents and enhanced participation in research studies, thereby impacting the future design of HSCT research protocols.