Citations

Abstract Background Immunosuppression following solid organ transplantation is a known risk factor for the development of posttransplant lymphoproliferative disorders (PTLD). Primary cutaneous T‐cell lymphoma (CTCL) occurring in the posttransplant setting is rare, which has made comprehensive understanding of this disease challenging. This study aims to further characterize the spectrum of clinicopathologic features of CTCL in solid organ transplant recipients (SOTR). Methods A retrospective chart review was performed for SOTR who were diagnosed with CTCL at a multi‐site academic medical center from January 1, 1998, to December 31, 2013. Eight patients fulfilled the inclusion criteria and were included in this study. Data collected included patient demographics, transplanted organ, the time between transplant and CTCL diagnosis, clinical presentation and rash morphology, a histological subtype of CTCL, immunosuppression regimens, and patient status. Twelve diagnostic skin biopsies for five patients were examined and reviewed by a board‐certified dermatopathologist. Results Six (75%) out of the eight patients were men, two (25%) were women, and the median age was 53 years. The median time from the date of transplant to the diagnosis of CTCL was 8.2 years. Transplanted organs included the liver (4), kidney (3), and heart (1). Clinical presentation varied from papulonodules, comedone‐like lesions, intense pruritis, and scaly erythematous eruptions. The most common histologic presentation was folliculotropic mycosis fungoides (FMF) (7/12). Epstein–Barr virus‐in situ hybridization (EBV‐ISH) was negative in all specimens. Conclusions We emphasize the rarity of CTCL among SOTR. Although rare in the general population, the FMF subtype appears to be disproportionately seen in SOTR compared with other CTCL.

7573 Background: While most patients (pts) with follicular lymphoma (FL) usually have favorable outcomes, those with refractory disease after first-line anti-CD20 based immunochemotherapy (IC), or progression within 24 months of diagnosis (POD24) have higher risk of premature death. There are no standard approaches for treating this vulnerable group and studies testing novel agents are ongoing in this setting. We sought to investigate clinical practice treatment choices and efficacy for pts with POD24 that align with eligibility criteria for the randomized SWOG1608 which compares IC with novel agents in this population. Methods: This was a multicenter observational cohort study from the LEO Consortium. Eligible pts had grade 1-3a FL diagnosed between 1/1/2002 and 2/1/2019, and initiated therapy after POD24 to first-line bendamustine or CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) based IC. Observation, radiotherapy, or rituximab monotherapy were permitted prior to IC and pts with transformation prior to the subsequent therapy after IC were excluded as per S1608. Outcomes of interest were overall and complete response rate (ORR/CR), progression-free survival (PFS), and overall survival (OS). Results: We identified 196 eligible pts with early progression to IC (39% antiCD20 Benda; 61% antiCD20 CHOP) who received subsequent therapy. Median age at post IC treatment was 57 years, 78% grade 1-2 FL. Treatments for pts with POD24 included CHOP- or Benda-based in 31%, salvage/hematopoietic stem cell transplant (HSCT) in 27%, novel therapies in 10% (including phosphatidylinositol 3-kinase inhibitors), antiCD20 monotherapy in 9%, and lenalidomide-based treatment in 8% (table); 21% of pts were treated on clinical trials. Across all treatments, ORR (CR) was 63% (37%) (95% CI: 55-70). At a median follow up of 6.2 years, 2 year PFS was 22% (95% CI: 17%-29%) and 5 year OS was 71% (95% CI: 65-79). Outcomes by regimen are shown in the table. Conclusions: Pts with FL experiencing POD24 following first-line IC are treated heterogeneously, with many pts still receiving IC as subsequent therapy. Despite modest CR rates and low 2-year PFS, 5-year OS appear to be improving compared to historical outcomes. This supports the ongoing need to investigate novel treatments in this population. [Table: see text]

Background: Track & field has more participants compared to any other high school sport and continues to gain popularity among middle school aged kids. Among many events, hurdles is unique because there is continued running with repeated jumping over an apparatus. Although serious injury has been anecdotally reported, there are few studies describing pediatric hurdle injuries including sex and age differences. Purpose: To investigate hurdle-related injury types and body locations based on age and sex among children and adolescents. Methods: Hurdle related injury data was extracted from the National Electronic Injury Surveillance System (NEISS), which represents emergency room visits. The search period was a 10-years (2008-2017). The eligibility criteria was < 18 years of age. Injuries were then classified based upon injury type and body location(s) involved. A chi-square (x2) analysis was employed to assess proportional differences of top three hurdle related injury types and body locations by age (<14 years vs. >15 years) and sex (male vs. female). Statistical significance was set as p<0.05. Results: A total of 749 cases related to hurdle injuries were extracted. Among recorded 749 injuries, traumatic fractures (N=218, 29.1%), joint sprain (N=191, 25.5%), and contusion/hematoma/bruise (N=78, 10.4%) were found as the top three most commonly sustained injuries. Chi-square (x2)analysis found more traumatic fractures in <14 years (34.1%) compared to >15 years (21.5%, p=0.001) while more joint sprain was identified in >15 years (29.6%) than <14 years (22.8%, p=0.036). Regarding sex comparisons, males had more traumatic fractures (35.1%) than females (24.3%, p=0.001). Conversely, females sustained more joint sprains (29.1%) and contusion/hematoma/bruise (12.7%) than males (joint sprain, 21.0%, p=0.012; contusion/hematoma/bruise, 7.5%, p=0.020). The top 3 injured body locations were ankle (N=140, 18.7%), knee (N=120, 16.0%), and wrist (N=69, 9.2%). No differences were found between body locations and age; however, statistical differences were detected by sex comparisons. Ankle injury was more common in females (24.0%) than males (12.0%, p=0.001). Yet, injury at wrist was more prevalent in males (11.7%) compared to females (7.2%, p=0.034). Conclusion: Findings of this study suggest that hurdle injury types seen in the emergency room differ by sex and age: more fractures are seen in males and younger pediatric populations while more sprains are seen in females and older adolescents. These findings may be helpful in event planning and may also play a role in injury prevention.

Background Extracellular DNA traps (ETs) have important implications in both thrombosis and thrombolysis. Thus, developing benchtop thrombus analogs that recapitulate clinical ETs is potentially of great value for preclinical development and testing of thrombolytic agents and thrombectomy devices. In this study, we aimed to develop ETs-rich thrombus analogs for preclinical testing. Methods Red blood cell (RBC)-rich, fibrin-rich, and platelet-rich thrombus analogs were created using human whole blood, platelet-poor plasma, and platelet-rich plasma obtained from the blood bank following institutional approval. Peripheral blood mononuclear cells (9.9×106 cells/mL) isolated from human whole blood and lipopolysaccharide (1 µg/mL) were added to induce ETs. Histochemical, immunohistochemistry and immunofluorescence were used to identify thrombus components and ETs. Scanning electronic microscopy was used to investigate the ultrastructure of the thrombus analogs. The thrombus compositions, morphologic features of ETs and citrullinated histone H3 (H3Cit) expression were compared with those of thrombi retrieved from patients by thrombectomy. Results ETs-rich thrombus analogs were more compacted th-an the ETs-poor thrombus analogs. ETs were identified in both ETs-rich thrombus analogs and patient thrombi showing morphologic features including nuclear lobulation, nuclear swelling, diffused chromatin within cytoplasm, DNA/chromatin extending intracellularly and extracellularly, and extracellular chromatin patches and bundles. In the ETs-poor thrombus analogs, ETs were not observed and H3Cit expression was absent to minimal. The compositions and H3Cit expression in the ETs-rich thrombus analogs fell in the range of patient thrombi. Conclusions ETs-rich thrombus analogs can be consistently created in vitro and may benefit the preclinical development and testing of new thrombolytic agents and thrombectomy devices.

AbstractOraxol consists of an oral dosage form of the chemotherapeutic agent paclitaxel administered with a novel P‐glycoprotein inhibitor encequidar methanesulfonate monohydrate (formerly named HM30181A), which allows oral treatment of cancers that would otherwise be treated with intravenous paclitaxel. Here we describe the population pharmacokinetics (popPK) analyses for oral paclitaxel in patients with advanced/metastatic solid tumors to characterize pharmacokinetic (PK) profiles and quantify sources of PK variability. The best fit popPK model for oral paclitaxel, based on data from seven clinical studies (197 patients with advanced/metastatic solid tumors), involves a linear two‐compartment structural model containing first‐order absorption with a short lag time and first‐order elimination as well as a log additive error. In this popPK model, lower population estimates of central volume for Asian patients versus Caucasian patients did not translate into clinical meaningful differences in oral paclitaxel exposure. Age, sex, body weight or surface area, mild hepatic impairment, and mild to moderate renal impairment had no clinically meaningful effects on the systemic exposure of oral paclitaxel. Simulations were performed on clinical therapeutic dose (oral paclitaxel 205 mg/m2 once daily ×3 days per week) to predict exposure of oral paclitaxel and to support treatment benefits observed in a pivotal phase III trial.

Abstract Study Objectives Objective excessive daytime sleepiness (EDS) is associated with systemic inflammation and a higher risk of cardiometabolic morbidity in obstructive sleep apnea (OSA). We hypothesized that OSA with objective EDS is associated with higher levels of sympathetic nerve activity (SNA) when compared with self-reported EDS. We, therefore, examined the associations between objective and self-reported EDS with SNA in patients with OSA. Methods We studied 147 consecutive male patients with OSA from the institutional sleep clinic. Objective EDS and self-reported EDS were defined based on Multiple Sleep Latency Test (MSLT) latency ≤ 8 minutes and Epworth Sleepiness Scale (ESS) &gt; 10, respectively. Twenty-four-hour urinary norepinephrine was used for assessing SNA. Blood pressure (BP) was measured both in the evening and in the morning. Results Twenty-four-hour urinary norepinephrine was significantly higher in patients with OSA with objective EDS compared with those without objective EDS (p = 0.034), whereas it was lower in patients with OSA with self-reported EDS compared with those without self-reported EDS (p = 0.038) after adjusting for confounders. Differences in the sympathetic drive were most striking in those with an objective but not self-reported EDS versus those with self-reported but not objective EDS (p = 0.002). Moreover, shorter MSLT latency was significantly associated with higher diastolic BP (β = −0.156, p = 0.049) but not systolic BP. No significant association between ESS scores and BP was observed. Conclusions Objective, but not self-reported EDS, is associated with increased SNA and diastolic BP among males with OSA, suggesting that objective EDS is a more severe phenotype of OSA that is accompanied by higher sympathetic drive, higher BP, and possibly greater cardiovascular morbidity and mortality.

Introduction: Numerous endovascular tools exist for the treatment of intracranial aneurysms with an increased use of flow-diverting devices in recent years. However, the biological mechanisms leading to aneurysm healing or potential complications such as delayed aneurysm ruptures after flow-diverter treatment are not yet well established. We used RNA-sequencing technology to identify genes relevant for biological impact of coils and flow-diverters in elastase-induced saccular aneurysms in rabbits and to identify genes and pathways of potential clinical interest. Methods: Elastase-induced saccular aneurysms were created at the origin of the right common carotid artery. Aneurysms were treated with coils (n=5) or flow-diverters (Pipeline Embolic Device, Covidien, CA) (n=4). Untreated aneurysms (n=6) were used as controls. Messenger RNA and microRNA were isolated from the aneurysms at 4 weeks following treatment. RNA samples were processed using RNA-seq technology. RNA-seq results were analyzed by using the Ingenuity Pathway Analysis tool. Results: Using RNA sequencing for coiled versus non-treated aneurysms, 464 genes were found to be differentially expressed with 58 genes down regulated and 406 genes up regulated. Using the same criteria for the flow-diverter treated aneurysms, 177 genes were found to be differentially expressed with 8 genes down regulated and 169 genes up regulated. Comparing coiled versus flow-diverter treated aneurysms, 13 genes were significantly differentially expressed with 8 down regulated and 5 up regulated genes. Genes identified with the highest interest for aneurysms healing were fibroblast growth factor-23, matrix metalloproteinases (MMP)-1, Scinderin and Basigin (implicated in MMP-2 and MMP-9 regulation). Pathway analysis associated these genes with inflammatory response, cellular migration, and coagulation, among other functions. Conclusions: RNA-sequencing analysis of rabbit aneurysms revealed differential regulation of some key pathways, including inflammation and cellular migration that could explain the different biological mechanisms implicated in aneurysms healing either after coiling or flow-diverter treatments and could explain potential device-related complications.

Backgound and Purpose: Mechanisms of both healing and complications, including spontaneous aneurysm rupture, remain unclear following flow diverter treatment. The aim of the current study was to compare the gene expression of various key molecules involved in the healing of aneurysms between aneurysms treated with microcoils and flow diverters. Methods: Saccular aneurysms were created in rabbits (n=12). Aneurysms were either treated with coils (n=6) or with flow diverters (n=6). Aneurysm tissue was harvested at four weeks following treatment and used for gene expression and zymography experiments. Genes with a fold change of 1.2 or greater were considered up regulated, whereas those with a fold change of 0.8 or less were considered down regulated. Results: All coil embolized aneurysms were completely occluded at follow up. Two aneurysms were occluded and the remaining four samples were incompletely occluded in the flow diverter treated group. The following genes were expressed at lower levels in the flow diverter group as compared to the coiled aneurysm group: genes encoding proteinases (matrix metalloproteinases -2 and -9), cellular markers (endothelial nitric oxide synthase and smooth muscle actin), and structural proteins (collagens and fibronectin). Genes related to inflammation (tumor necrosis factor-α and monocyte chemoattractant protein -1) were up regulated in flow diverter treated aneurysms compared to coil embolized aneurysms. Notably, the enzymatic activity of active MMP-9 was high in aneurysms treated with flow diverters. Conclusion: As compared to coiled aneurysms, the molecular milieu surrounding aneurysms treated with flow diverters is characterized by higher levels of activated proteases, elevated expression of genes encoding inflammatory proteins, and diminished expression of genes encoding structural proteins. These data may provide improved understanding of rupture risk and healing following aneurysm treatment, and inform development of therapies aimed at lowering rupture risk and accelerating healing.

Abstract Senescent cells drive age-related tissue dysfunction partially via the induction of a chronic senescence-associated secretory phenotype (SASP). Mitochondria are major regulators of the SASP; however, the underlying mechanisms have not been elucidated. Mitochondria also control apoptosis, a cell fate generally perceived as distinct from cellular senescence, which is apoptosis resistant. Here, we show that mitochondrial outer membrane permeability (MOMP) occurring in a small subset of mitochondria is a feature of cellular senescence. This process, called minority MOMP (miMOMP), depends on the formation of BAX and BAK macropores and results in release of mitochondrial DNA (mtDNA) into the cytosol, which in turn activates the cGAS/STING pathway, a major regulator of the SASP. Importantly, we found that inhibition of MOMP in vivo decreases inflammatory markers and improves healthspan parameters in aged mice. Our results propose the novel concept that apoptosis and senescence are regulated by similar mitochondrial-dependent mechanisms, and that sub-lethal mitochondrial apoptotic stress is a major driver of the SASP. We also provide proof-of-concept that inhibition of miMOMP may be a new therapeutic avenue to improve healthspan.