Developmental and therapeutic implications of IL4ra expression for rhabdomyosarcoma.

Rhabdomyosarcoma (RMS) is a solid tumor whose metastatic progression can be accelerated through interleukin-4 receptor alpha (Il4ra) mediated interaction with normal muscle stem cells (satellite cells). To understand the function of Il4ra in this tumor initiation phase of RMS, we conditionally deleted Il4ra in genetically-engineered RMS mouse models. Nullizygosity of Il4ra altered the latency, site and/or stage distribution of RMS tumors compared to IL4RA intact models. Primary tumor cell cultures taken from the genetically-engineered models then used in orthotopic allografts further defined the interaction of satellite cells and RMS tumor cells in the context of tumor initiation: in alveolar rhabdomyosarcoma (ARMS), satellite cell co-injection was necessary for Il4ra null tumor cells engraftment, whereas in embryonal rhabdomyosarcoma (ERMS), satellite cell co-injection decreased latency of engraftment of Il4ra wildtype tumor cells but not Il4ra null tumor cells. When refocusing on Il4ra wildtype tumors by single cell sequencing and cytokine studies, we have uncovered a putative signaling interplay of Il4 from T-lymphocytes being received by Il4ra + rhabdomyosarcoma tumor cells, which in turn express Ccl2, the ligand for Ccr2 and Ccr5. Taken together, these results suggest that mutations imposed during tumor initiation have different effects than genetic or therapeutic intervention imposed once tumors are already formed. We also propose that CCL2 and its cognate receptors CCR2 and/or CCR5 are potential therapeutic targets in Il4ra mediated RMS progression.

Mechanical circulatory support versus vasopressors alone in patients with acute myocardial infarction and cardiogenic shock undergoing percutaneous coronary intervention.

BACKGROUND: Previous studies have compared Impella use to intra-aortic balloon pump (IABP) use in patients with acute myocardial infarction and cardiogenic shock (AMI-CS) undergoing percutaneous coronary intervention (PCI). Our objective was to compare clinical outcomes in patients with AMI-CS undergoing PCI who received Impella (percutaneous left ventricular assist device) without vasopressors, IABP without vasopressors, and vasopressors without mechanical circulatory support (MCS). METHODS: We queried the National Inpatient Sample (NIS) using ICD-10 codes (2015-2018) to identify patients with AMI-CS undergoing PCI. We created three propensity-matched cohorts to examine clinical outcomes in patients receiving Impella versus IABP, Impella versus vasopressors without MCS, and IABP versus vasopressors without MCS. RESULTS: Among 17,762 patients, Impella use was associated with significantly higher in-hospital major bleeding (31.4% vs. 13.6%; p < 0.001) and hospital charges (p < 0.001) compared to IABP use, with no benefit in mortality (34.1% vs. 26.9%; p = 0.06). Impella use was associated with significantly higher mortality (42.3% vs. 35.7%; p = 0.02), major bleeding (33.9% vs. 22.7%; p = 0.001), and hospital charges (p < 0.001), when compared to the use of vasopressors without MCS. There were no significant differences in clinical outcomes between IABP use and the use of vasopressor without MCS. CONCLUSIONS: In this analysis of retrospective data of patients with AMI-CS undergoing PCI, Impella use was associated with higher mortality, major bleeding, and in-hospital charges when compared to vasopressor therapy without MCS. When compared to IABP use, Impella was associated with no mortality benefit, along with higher major bleeding events and in-hospital charges. A vasopressor-only strategy suggested no difference in clinical outcomes when compared to IABP. This study uses the NIS for the first time to highlight outcomes in AMI-CS patients undergoing PCI when treated with vasopressor support without MCS, compared to Impella and IABP use.

Pediatric ERCP: Factors for Success and Complication-A 17-Year, Multisite Experience.

OBJECTIVES: Endoscopic retrograde cholangiopancreatography (ERCP) is an increasingly utilized procedure in pediatric populations. A lack of dedicated pediatric research has led endoscopists to extrapolate adult risk factors and preventative strategies to children. The aim of this multisite, retrospective study was to identify risks for adverse events, procedure failure, and prolonged courses in pediatric patients undergoing ERCP. METHODS: Pediatric patients who had an ERCP at one of our academic centers were identified by query of their electronic medical records. Pre-procedure and post-procedure data were collected with ERCP-related adverse events defined according to the consensus criteria developed by Cotton et al 2010. RESULTS: Between January 2004 and January 2021, 287 children had a total of 716 ERCPs. The procedure success rate was 95.5% with no mortality and an adverse event rate of 12.7%. Younger age was associated with increased case complexity, increased adverse events, and an increased rate of repeat ERCP. Case complexity score correlated with increased procedure time ( P < 0.001) and increased adverse events (tau 0.24, P < 0.01); stent removal and pancreatic stenting were more likely to precede an adverse event. Pancreatitis, pancreatic divisum, and pancreatic stricture/stenosis were associated with increased adverse events and rates of repeat ERCP. CONCLUSIONS: Pediatric ERCP adverse event rates are higher than adults. The complexity grading system proposed by the Cotton et al appears to have applicability to pediatric patients. Young age and interventions affecting the pancreatic duct are associated with adverse ERCP outcomes in pediatrics.

Modulation of autophagy: a Phase II study of vorinostat plus hydroxychloroquine versus regorafenib in chemotherapy-refractory metastatic colorectal cancer (mCRC).

BACKGROUND: In metastatic colorectal cancer (mCRC), regorafenib (RGF), a multi-kinase inhibitor with angiogenic inhibition has modest effects on survival. We reported that autophagy modulation using hydroxychloroquine (HCQ), enhances the anticancer activity of the histone deacetylase inhibitor, vorinostat (VOR), in mCRC, is well tolerated, and has comparable activity to RGF. Thus, we conducted a prospective study of VOR/HCQ versus RGF in mCRC. METHODS: This is a randomised, controlled trial of VOR 400 mg and HCQ 600 mg orally daily versus RGF 160 mg orally daily (3 weeks on/1 week off), every 4 weeks, in patients with mCRC. PRIMARY ENDPOINT: median progression-free survival (mPFS). Secondary endpoints: median overall survival (mOS); adverse events; pharmacodynamic analyses. RESULTS: From 2/2015-10/2017, 42 patients were randomised to VOR/HCQ and RGF. Median age was 58.4 years. mPFS on VOR/HCQ was 1.9 months versus 4.35 months with RGF (P = 0.032). There was no difference in mOS (P = 0.9). Treatment was tolerated in both arms. In both arms, there was improved anti-tumour immunity. CONCLUSIONS: VOR/HCQ had an inferior PFS when compared to RGF, although there was an increase in anti-tumour immunity in mCRC. VOR/HCQ has a favourable safety profile, and immune or tumour biomarkers may be used to identify clinical benefit of autophagy modulation in mCRC. CLINICAL TRIAL REGISTRATION: NCT02316340.

Sensitization of osteosarcoma to irradiation by targeting nuclear FGFR1.

Over the past 25 years, chemotherapy regimens for osteosarcoma have failed to improve the 65-70% long-term survival rate. Radiation therapy is generally ineffective except for palliative care. We here investigated whether osteosarcoma can be sensitized to radiation therapy targeting specific molecules in osteosarcoma. Large-scale RNA sequencing analysis in osteosarcoma tissues and cell lines revealed that FGFR1 is the most frequently expressed receptor tyrosine kinase in osteosarcoma. Nuclear FGFR1 (nFGFR1) was observed by subcellular localization assays. The functional studies using a FGFR1IIIb antibody or small molecule FGFR1 inhibitors showed that nFGFR1, but not membrane-bound FGFR1, induces G2 cell-cycle checkpoint adaptation, cell survival and polyploidy following irradiation in osteosarcoma cells. Further, the activation of nFGFR1 induces Histone H3 phosphorylation at Ser 10 and c-jun/c-fos expression to contribute cell survival rendering radiation resistance. Furthermore, an in vivo mouse study revealed that radiation resistance can be reversed by the inhibition of nFGFR1. Our findings provide insights into the potential role of nFGFR1 to radiation resistance. Thus, we propose nFGFR1 could be a potential therapeutic target or a biomarker to determine which patients might benefit from radiation therapy.

Bromodomain 4 inhibition leads to MYCN downregulation in Wilms tumor.

BACKGROUND: Wilms tumor is the most common childhood kidney cancer. Two distinct histological subtypes of Wilms tumor have been described: tumors lacking anaplasia (the favorable subtype) and tumors displaying anaplastic features (the unfavorable subtype). Children with favorable disease generally have a very good prognosis, whereas those with anaplasia are oftentimes refractory to standard treatments and suffer poor outcomes, leading to an unmet clinical need. MYCN dysregulation has been associated with a number of pediatric cancers including Wilms tumor. PROCEDURES: In this context, we undertook a functional genomics approach to uncover novel therapeutic strategies for those patients with anaplastic Wilms tumor. Genomic analysis and in vitro experimentation demonstrate that cell growth can be reduced by modulating MYCN overexpression via bromodomain 4 (BRD4) inhibition in both anaplastic and nonanaplastic Wilms tumor models. RESULTS: We observed a time-dependent reduction of MYCN and MYCC protein levels upon BRD4 inhibition in Wilms tumor cell lines, which led to cell death and proliferation suppression. BRD4 inhibition significantly reduced tumor volumes in Wilms tumor patient-derived xenograft (PDX) mouse models. CONCLUSIONS: We suggest that AZD5153, a novel dual-BRD4 inhibitor, can reduce MYCN levels in both anaplastic and nonanaplastic Wilms tumor cell lines, reduces tumor volume in Wilms tumor PDXs, and should be further explored for its therapeutic potential.

Lineage of origin in rhabdomyosarcoma informs pharmacological response.

Lineage or cell of origin of cancers is often unknown and thus is not a consideration in therapeutic approaches. Alveolar rhabdomyosarcoma (aRMS) is an aggressive childhood cancer for which the cell of origin remains debated. We used conditional genetic mouse models of aRMS to activate the pathognomonic Pax3:Foxo1 fusion oncogene and inactivate p53 in several stages of prenatal and postnatal muscle development. We reveal that lineage of origin significantly influences tumor histomorphology and sensitivity to targeted therapeutics. Furthermore, we uncovered differential transcriptional regulation of the Pax3:Foxo1 locus by tumor lineage of origin, which led us to identify the histone deacetylase inhibitor entinostat as a pharmacological agent for the potential conversion of Pax3:Foxo1-positive aRMS to a state akin to fusion-negative RMS through direct transcriptional suppression of Pax3:Foxo1.

Age-associated genes in human mammary gland drive human breast cancer progression.

BACKGROUND: Aging is a comorbidity of breast cancer suggesting that aging-associated transcriptome changes may promote breast cancer progression. However, the mechanism underlying the age effect on breast cancer remains poorly understood. METHOD: We analyzed transcriptomics of the matched normal breast tissues from the 82 breast cancer patients in The Cancer Genome Atlas (TCGA) dataset with linear regression for genes with age-associated expression that are not associated with menopause. We also analyzed differentially expressed genes between the paired tumor and non-tumor breast tissues in TCGA for the identification of age and breast cancer (ABC)-associated genes. A few of these genes were selected for further investigation of their malignancy-regulating activities with in vitro and in vivo assays. RESULTS: We identified 148 upregulated and 189 downregulated genes during aging. Overlapping of tumor-associated genes between normal and tumor tissues with age-dependent genes resulted in 14 upregulated and 24 downregulated genes that were both age and breast cancer associated. These genes are predictive in relapse-free survival, indicative of their potential tumor promoting or suppressive functions, respectively. Knockdown of two upregulated genes (DYNLT3 and P4HA3) or overexpression of the downregulated ALX4 significantly reduced breast cancer cell proliferation, migration, and clonogenicity. Moreover, knockdown of P4HA3 reduced growth and metastasis whereas overexpression of ALX4 inhibited the growth of xenografted breast cancer cells in mice. CONCLUSION: Our study suggests that transcriptome alterations during aging may contribute to breast tumorigenesis. DYNLT3, P4HA3, and ALX4 play significant roles in breast cancer progression.

Serum microRNA profiles among dioxin exposed veterans with monoclonal gammopathy of undetermined significance.

Previously an increased risk for monoclonal gammopathy of undetermined significance (MGUS), a precursor of multiple myeloma (MM), was reported among Vietnam veterans exposed to Agent Orange and its contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Dysregulated expression of certain microRNAs (miRNAs) was demonstrated in MGUS and MM. Given the important role of miRNAs in cellular homeostasis, the aim of this study was to determine if there was an association between serum levels of selected miRNAs and TCDD in 47 MGUS cases identified in our previous investigation using serum specimens and exposure data archived by the Air Force Health Study (AFHS). A total of 13 miRNA levels (let-7a, let-7i, miR-16, miR-20a, miR-21, miR-34a, miR-106b, miR-146a, miR-181a, miR-192, miR-205, miR-335, and miR-361) was measured in serum stored during the 2002 AFHS follow-up and the relationship to lipid-adjusted serum TCDD levels in 1987 was determined. miR-34a showed the strongest relationship with TCDD; after age-adjustment, this positive association was more pronounced. In contrast, the other 12 miRNAs displayed absolute values of age adjusted coefficient estimates below 1.16 and non-significant p-values. The observed strong positive association between high body burdens of TCDD and miR-34a, a tumor suppressor regulated by p53, in this MGUS population warrants clarification of the TCDD-miR-34a relationship and its role in the pathogenesis of MGUS and risk for MM.

Probabilistic modeling of personalized drug combinations from integrated chemical screen and molecular data in sarcoma.

BACKGROUND: Cancer patients with advanced disease routinely exhaust available clinical regimens and lack actionable genomic medicine results, leaving a large patient population without effective treatments options when their disease inevitably progresses. To address the unmet clinical need for evidence-based therapy assignment when standard clinical approaches have failed, we have developed a probabilistic computational modeling approach which integrates molecular sequencing data with functional assay data to develop patient-specific combination cancer treatments. METHODS: Tissue taken from a murine model of alveolar rhabdomyosarcoma was used to perform single agent drug screening and DNA/RNA sequencing experiments; results integrated via our computational modeling approach identified a synergistic personalized two-drug combination. Cells derived from the primary murine tumor were allografted into mouse models and used to validate the personalized two-drug combination. Computational modeling of single agent drug screening and RNA sequencing of multiple heterogenous sites from a single patient's epithelioid sarcoma identified a personalized two-drug combination effective across all tumor regions. The heterogeneity-consensus combination was validated in a xenograft model derived from the patient's primary tumor. Cell cultures derived from human and canine undifferentiated pleomorphic sarcoma were assayed by drug screen; computational modeling identified a resistance-abrogating two-drug combination common to both cell cultures. This combination was validated in vitro via a cell regrowth assay. RESULTS: Our computational modeling approach addresses three major challenges in personalized cancer therapy: synergistic drug combination predictions (validated in vitro and in vivo in a genetically engineered murine cancer model), identification of unifying therapeutic targets to overcome intra-tumor heterogeneity (validated in vivo in a human cancer xenograft), and mitigation of cancer cell resistance and rewiring mechanisms (validated in vitro in a human and canine cancer model). CONCLUSIONS: These proof-of-concept studies support the use of an integrative functional approach to personalized combination therapy prediction for the population of high-risk cancer patients lacking viable clinical options and without actionable DNA sequencing-based therapy.

Chronic total occlusions-Is true lumen wire passage preferred to subintimal dissection re-entry?

True lumen crossing is superior to subintimal crossing. Subintimal versus true lumen crossing may only be apparent if IVUS is performed. Newer techniques for true lumen crossing need to be developed.

Acute kidney injury in patients undergoing endovascular therapy for critical limb ischemia.

BACKGROUND: Similar to coronary angiography and interventions, patients undergoing percutaneous treatment of lower extremity peripheral arterial disease are also at risk of acute kidney injury (AKI). The incidence, risk factors associations, need for dialysis and inhospital mortality related to AKI in patients with critical limb ischemia (CLI) following endovascular therapy is poorly defined. OBJECTIVES: The purpose of this study was to analyze data from the National Inpatient Sample (NIS) to determine the aforementioned outcomes in patients with CLI. METHODS: Using the full NIS admission dataset from 2003 through 2012, ICD-9 codes relevant to comorbid conditions, procedure codes, composite codes for AKI, and inhospital mortality were analyzed using multivariate models. RESULTS: A total of 273,624 patients were included with a mean age of 70.0 ± 27.4 years, 46.0% were female, 57.2% had diabetes, 43.4% had coronary artery disease (CAD), and 29.2% had chronic kidney disease (CKD). The overall rate of AKI was 10.4%, and there was a temporal rise over the analysis period in AKI incidence (p < .001). Age, diabetes, CKD, and heart failure were all associated with AKI (p < .0001). The inhospital mortality rate in the patients with AKI declined over time but was higher than in patients without AKI (6.0% vs. 1.4%), p < .0001. The mortality rate was substantially higher in patients with AKI requiring dialysis as compared to AKI not requiring dialysis (13.4% vs. 5.6%), p < .0001. CONCLUSIONS: AKI is associated with age, CKD, and heart failure. The incidence of AKI following endovascular therapy for CLI is rising and independently associated with inhospital mortality.

Pilot Study to Evaluate the Adjunct Use of a Povidone-Iodine Topical Antiseptic in Patients with Soft Tissue Abscesses.

BACKGROUND: Povidone-iodine (PVP-I) antiseptic solutions have been shown to be effective against methicillin-resistant Staphylococcal aureus, a common cause of superficial skin abscesses. OBJECTIVES: Our objective was to study the feasibility of using PVP-I as a treatment adjunct in patients with superficial skin abscesses and determine if it confers any benefit over incision and drainage (I&D) alone. METHODS: This was a randomized controlled pilot study of adult patients with an uncomplicated skin abscess. Patients were randomized to PVP-I or standard treatment. All patients had I&D and abscess packing. Patients randomized to PVP-I were instructed on daily application of the agent to hands, wound, and surrounding skin with dressing changes. Subjects returned at 48-72 h and 7-10 days and followed-up by phone at 30 days. The primary outcome was clinical cure 7-10 days after I&D. The secondary outcomes were rate of development of new skin lesions and spread in household contacts within 30 days. RESULTS: Clinical cure occurred in 91.3% of patients in the standard group vs. 88.2% of patients in the PVP-I group (difference, 3.1%; 95% confidence interval [CI] -10.7 to 16.8; p = 0.53). There was a significantly higher adverse event rate in the group who received PVP-I (59.6%) vs. standard care (26.5%) (difference 33.1%, 95% CI 13.2-50.2; p < 0.001). CONCLUSIONS: There was no difference in clinical cure rates among patients using PVP-I (88.2%) vs. standard care (91.3%) after I&D. There were no major adverse events, but the addition of PVP-I was commonly associated with local skin irritation.

Internal Mammary Lymph Node Biopsy During Free-Flap Breast Reconstruction: Optimizing Adjuvant Breast Cancer Treatment Through Comprehensive Staging.

BACKGROUND: Accurate breast cancer staging is essential for optimal management of adjuvant therapies. While breast lymphatic drainage involves both axillary and internal mammary (IM) lymph node (LN) basins, IM LN sampling is not routinely advocated. The current study analyzes the incidence of IM LN metastases sampled during free flap breast reconstruction and subsequent changes in adjuvant treatment. METHODS: A retrospective analysis of patients with positive IM LN biopsies during free flap breast reconstruction was performed. Pre-reconstruction surgical and adjuvant therapies as well as staging and prognostic data were recorded. Change in adjuvant therapies based solely on IM LN positivity was determined. RESULTS: IM LN metastases were found on 28 (1.3%) out of 2057 patients and comprised the study population. Mean age was 49 years with pre-reconstruction chemotherapy or radiation administered in 50 or 54% of cases, respectively. Five (18%) patients had previously undergone lumpectomy with axillary sampling. Mean tumor size was 3.1 cm with tumor location evenly distributed among all four quadrants. Ten (36%) patients had isolated IM LN metastases Patients with both axillary and IM disease had larger lesions, increased prevalence of pre-reconstruction chemotherapy and radiation. Based exclusively on positive IM LN disease, 17 (63%) patients had a change in adjuvant therapy. CONCLUSION: Despite the low incidence of IM LN metastases, IM LN biopsy during free flap breast reconstruction is recommended. In 36% of cases, nodal metastases were isolated to the IM nodes. Identification of IM metastases influenced adjuvant therapies in a majority of cases.

A comparison of preoperative and intraoperative vein mapping sizes for arteriovenous fistula creation.

BACKGROUND: Duplex ultrasound (DUS) mapping of the veins and arteries of the upper extremity is a well-established practice in arteriovenous fistula creation for long-term hemodialysis access. Previous publications have shown that vein diameters varying from 2 to 3 mm are predictive of success. Regional anesthesia is known to result in vasodilation and thus to increase the diameter of upper extremity veins. This study compares the sizes of veins measured by preoperative DUS mapping with those obtained after regional anesthesia to determine whether intraoperative DUS results in increased vein diameters and thus changes in the operative plan. A second goal was to determine whether such changes resulted in functional access. METHODS: This was a prospective observational study conducted between July 2013 and December 2014. Consecutive patients were preoperatively mapped and then intraoperatively mapped after administration of a regional anesthetic. Comparison of vein mapping sizes and comparison of preoperative plan and operative procedure based on the preoperative and intraoperative DUS mapping, respectively, were analyzed with a repeated-measures linear model. Significance testing was two sided, with a significance level of 5%. RESULTS: Sixty-five patients with end-stage renal disease underwent placement of arteriovenous access with preoperative and intraoperative DUS mapping after regional anesthesia. Comorbidities were representative of the vascular population. After regional anesthesia, intraoperative mid forearm and distal forearm cephalic veins were significantly larger than their respective preoperative measurements. Average increase in diameter of the mid forearm cephalic vein and distal forearm was 0.96 mm (P < .001) and 0.50 mm (P = .04), respectively. There was a significant difference in the number and configuration of arteriovenous accesses (P < .0001). There was more than a twofold significant increase in radial artery-based access procedures concomitant with a significant reduction of brachial-based access procedures and a reduction in graft access procedures. Overall functional access rate was 63%, and patency rates were comparable to those reported in the literature. CONCLUSIONS: The routine use of intraoperative DUS mapping after regional anesthesia is recommended to determine the optimal access site for chronic hemodialysis access. Identifying additional access options not seen with physical examination and preoperative DUS mapping will provide end-stage renal disease patients with more fistula options and hence a longer access life span for a lifelong disease.

Pleural electrical impedance is a sensitive, real-time indicator of pneumothorax.

BACKGROUND: Chest tube management protocols, particularly in patients with alveolar-pleural air leak due to recent surgery or trauma, are limited by concerns over safety, especially concerns about rapid and occult development of pneumothorax. A continuous, real-time monitor of pneumothorax could improve the quality and safety of chest tube management. We developed a rat model of pneumothorax to test a novel approach of measuring electrical impedance within the pleural space as a monitor of lung expansion. MATERIALS AND METHODS: Anesthetized Sprague-Dawley rats underwent right thoracotomy. A novel impedance sensor and a thoracostomy tube were introduced into the right pleural space. Pneumothorax of varying volumes ranging from 0.2 to 20 mL was created by syringe injection of air via the thoracostomy tube. Electrical resistance measurements from the pleural sensor and fluoroscopic images were obtained at baseline and after the creation of pneumothorax and results compared. RESULTS: A statistically significant, dose-dependent increase in electrical resistance was observed with increasing volume of pneumothorax. Resistance measurement allowed for continuous, real-time monitoring of pneumothorax development and the ability to track pneumothorax resolution by aspiration of air via the thoracostomy tube. Pleural resistance measurement demonstrated 100% sensitivity and specificity for all volumes of pneumothorax tested and was significantly more sensitive for pneumothorax detection than fluoroscopy. CONCLUSIONS: The electrical impedance-based pleural space sensor described in this study provided sensitive and specific pneumothorax detection, which was superior to radiographic analysis. Real-time, continuous monitoring for pneumothorax has the potential to improve the safety, quality, and efficiency of postoperative chest tube management.

Evaluation of patritumab with or without erlotinib in combination with standard cytotoxic agents against pediatric sarcoma xenograft models.

BACKGROUND: Integrating molecularly targeted agents with cytotoxic drugs used in curative treatment of pediatric cancers is complex. An evaluation was undertaken with the ERBB3/Her3-specific antibody patritumab (P) either alone or with the ERBB1/epidermal growth factor receptor inhibitor erlotinib (E) in combination with standard cytotoxic agents, cisplatin, vincristine, and cyclophosphamide, in pediatric sarcoma xenograft models that express receptors and ligands targeted by these agents. PROCEDURES: Tumor models were selected based upon ERBB3 expression and phosphorylation, and ligand (heregulin) expression. Patritumab, E, or these agents combined was evaluated without or with concomitant cytotoxic agents using procedures developed by the Pediatric Preclinical Testing Program. RESULTS: Full doses of cytotoxic agents were tolerated when combined with P, whereas dose reductions of 25% (vincristine, cisplatin) or 50% (cyclophosphamide) were required when combined with P + E. Patritumab, E alone, or in combination did not significantly inhibit growth of any tumor model, except for Rh18 xenografts (E alone). Patritumab had no single-agent activity and marginally enhanced the activity of vincristine and cisplatin only in Ewing sarcoma ES-4. P + E did not increase the antitumor activity of vincristine or cisplatin, whereas dose-reduced cyclophosphamide was significantly less active than cyclophosphamide administered at its maximum tolerated dose when combined with P + E. CONCLUSIONS: P had no single-agent activity, although it marginally potentiated the activity of vincristine and cisplatin in one of three models studied. However, the addition of E necessitated dose reduction of each cytotoxic agent, abrogating the enhancement observed with P alone.

Continuous diffusion of oxygen improves diabetic foot ulcer healing when compared with a placebo control: a randomised, double-blind, multicentre study.

OBJECTIVE: The aim of this study was to assess whether continuous diffusion of oxygen improves healing in people receiving treatment for diabetic foot ulcers (DFU). METHOD: A double-blind, placebo control randomised study to receive either active continuous diffusion of oxygen (CDO) therapy using an active CDO device, or a fully operational placebo device without delivering oxygen. Patients were followed until closure or 12 weeks. Patients, caretakers, treating physicians and independent evaluators were blinded to the study arm. All patients received identical offloading, debridement, dressings and follow-up. RESULTS: We enrolled 146 people with DFUs (77% male, aged 56.3±12.4 years). A significantly higher proportion (195%) of DFUs healed in the CDO arm compared with placebo (32.4% versus 16.7%, p=0.033). The time to 50% DFU closure was significantly shorter in patients that received CDO therapy (mean 18.4 versus 28.9 days, p=0.001). There were no differences in overall adverse events (p=0.66) or ulcer-related adverse events (p=0.30) in the active and placebo treatment groups. The relative performance of active CDO over placebo became greater when used in larger wounds (273%), in more chronic wounds (334%) and in weight bearing wounds (465%). CONCLUSION: The results of this study demonstrate that CDO leads to higher proportion of healed DFUs (p=0.033) and a faster time to closure compared with placebo in people with DFUs (p=0.015). Relative performance did not vary significantly with wound size (p=0.80), but revealed better relative performance in more chronic wounds (p=0.008) and in weight-bearing wounds (p=0.003).

Risks and benefits of phase I liver dysfunction studies: should patients with severe liver dysfunction be included in these trials?

Introduction The goal of organ dysfunction Phase I trials is to characterize the safety and pharmacokinetics of novel agents in cancer patients with liver or kidney dysfunction, but the clinical benefit is not well established. Methods We reviewed 170 patients across 15 liver dysfunction studies at our institution, grouped based on the NCI-Organ Dysfunction Working Group criteria or Child-Pugh Score. Results The median survival for the entire cohort was two months and just one month amongst patients with severe liver dysfunction. Patients with normal or mild liver dysfunction, absence of tumor in liver, good performance status, higher serum albumin and lower bilirubin, aspartate transaminase and alkaline phosphatase had improved survival by univariate analysis. Serum albumin and liver function classification remained significant by multivariate analysis. Conclusion Given poor survival of patients with liver dysfunction, we need better criteria, such as albumin levels, for optimally selecting patients for liver dysfunction studies.

The Effect of Trabeculae Carneae on Left Ventricular Diastolic Compliance: Improvement in Compliance With Trabecular Cutting.

The role of trabeculae carneae in modulating left ventricular (LV) diastolic compliance remains unclear. The objective of this study was to determine the contribution of trabeculae carneae to the LV diastolic compliance. LV pressure-volume compliance curves were measured in six human heart explants from patients with LV hypertrophy at baseline and following trabecular cutting. The effect of trabecular cutting was also analyzed with finite-element model (FEM) simulations. Our results demonstrated that LV compliance improved after trabecular cutting (p < 0.001). Finite-element simulations further demonstrated that stiffer trabeculae reduce LV compliance further, and that the presence of trabeculae reduced the wall stress in the apex. In conclusion, we demonstrate that integrity of the LV and trabeculae is important to maintain LV stiffness and loss in trabeculae leads to more LV compliance.