Elizabeth Weihe

Bop encodes a muscle-restricted protein containing MYND and SET domains and is essential for cardiac differentiation and morphogenesis

Many transcription factors regulate specific temporal-spatial events during cardiac differentiation; however, the mechanisms that regulate such events are largely unknown. Using a modified subtractive hybridization method to identify specific genes that influence early cardiac development, we found that Bop is expressed specifically in cardiac and skeletal muscle precursors before differentiation of these lineages. Bop encodes a protein containing MYND and SET domains, which have been shown to regulate transcription by mediating distinct chromatin modifications. We show that m-Bop is a histone deacetylase–dependent transcriptional repressor. Targeted deletion of Bop in mice disrupted maturation of ventricular cardiomyocytes and interfered with formation of the right ventricle. Normal expression of Hand2, a transcription factor essential for right ventricular development, in cardiomyocyte precursors is dependent upon m-Bop. These results indicate that m-Bop is essential for cardiomyocyte differentiation and cardiac morphogenesis.

Platelet transfusions in infants with necrotizing enterocolitis do not lower mortality but may increase morbidity.

OBJECTIVE:Necrotizing enterocolitis (NEC), a serious multisystemic inflammatory disease most commonly seen in premature neonates, is often associated with thrombocytopenia. Infants with severe forms of NEC commonly have platelet counts of less than 50,000/mm3, occasionally less than 10,000/mm3. Despite an absence of data to support the practice, platelet transfusions are commonly used to maintain a certain arbitrary platelet count in an effort to prevent bleeding. As platelet transfusions contain a variety of bioactive factors including pro-inflammatory cytokines, we hypothesized that a higher number and volume of platelet transfusions would not be associated with an improvement in mortality or morbidity.STUDY DESIGN:A retrospective cohort analysis was conducted of the medical records of all infants between 1997 and 2001 with Bells Stage 2 or 3 NEC associated with platelet counts of <100,000/mm3. The medical records were evaluated for the following variables: platelet counts, number and volume of platelet transfusions, symptoms of bleeding, and hospital course. Mortality and development of short bowel syndrome and/or cholestasis were correlated to the total number and volume (total ml and ml/kg) of platelet transfusions. Differences between the outcome groups were compared using the independent t-test, Fishers exact test and Mann–Whitney tests.RESULTS:A total of 46 infants met the study criteria (gestational age 28±4 weeks and birth weight 1166±756 g, mean±SD). There were a total of 406 platelet transfusions administered to the study population. Of these, 151 (37.2%) were given in the presence of active bleeding, with 62% of these resulting in the cessation of bleeding within 24 hours. Other listed indications for platelet transfusions were hypovolemia and severe thrombocytopenia. On analysis of the entire cohort, there was no statistical improvement in either mortality or morbidity (short bowel syndrome and cholestasis) with greater number and/or volume of platelet transfusions. Furthermore, we found that infants who developed short bowel syndrome and/or cholestasis had been given a significantly higher number and volume of platelet transfusions when compared to those who did not have these adverse outcomes [median (minimum – maximum)−number of transfusions : 9 (0 to 33) vs 1.5 (0 to 20), p=0.010; volume of transfusions (ml/kg) : 121.5 (0 to 476.6) vs 33.2 (0 to 224.3), p=0.013].CONCLUSION:This retrospective analysis suggests that greater number and volume of platelet transfusions in infants with necrotizing enterocolitis are associated with greater morbidity in the form of short bowel syndrome and/or cholestasis without the benefit of lower mortality.

Severe Thrombocytopenia Predicts Outcome in Neonates with Necrotizing Enterocolitis

OBJECTIVE:Necrotizing enterocolitis (NEC) is a common and serious gastrointestinal disorder that predominately affects premature infants. Few prognostic indices are available to guide physicians through the expected course of the disease. We hypothesized that the degree and timing of onset of severe thrombocytopenia (platelet count <100,000/mm3) would be a predictor of adverse outcome and an indication for surgical intervention in infants with NEC.STUDY DESIGN:The clinical presentation and outcome of all infants with Bell stage II or III NEC treated at Texas Childrens Hospital between 1997 and 2001 were retrospectively reviewed. Patients were stratified into two groups based on the presence (Group1) or absence (Group 2) of severe thrombocytopenia (platelet count <100,000/mm3) within 3 days of a diagnosis of NEC. Differences between groups were compared using logistic regression to estimate adjusted odds ratios.RESULTS:A total of 91 infants met inclusion criteria (average birth weight 1288±135 g; average gestational age 29.0±3.0 weeks). Compared to infants in Group 2, infants in Group 1 were more premature (28.0±4.1 vs 30.0±4.2 weeks; p=0.02), more likely to have received postnatal steroids (42.5% vs 20.4%; p=0.02), and more likely to require laparotomy for gangrenous bowel (adjusted OR 16.33; p<0. 001). The presence of severe thrombocytopenia was also a predictor of mortality (adjusted OR 6.39; p=0.002) and NEC-related gastrointestinal complications including cholestatic liver disease and short bowel syndrome (adjusted OR 5.47; p=0.006).CONCLUSION:Severe thrombocytopenia within the first 3 days after a diagnosis of NEC suggests a higher likelihood of bowel gangrene, morbidity, and mortality. Prospective studies of infants with early and severe thrombocytopenia may help determine the optimal timing of laparotomy in infants with NEC.

Prospective CT Screening for Lung Cancer in a High-Risk Population: HIV-Positive Smokers

Background: Epidemiological evidence suggests that HIV-infected individuals are at increased risk of lung cancer, but no data exist because large computed tomography (CT) screening trials routinely exclude HIV-infected participants. Methods: From 2006 to 2013, we conducted the worlds first lung cancer screening trial of 224 HIV-infected current/former smokers to assess the CT detection rates of lung cancer. We also used 130 HIV-infected patients with known lung cancer to determine radiographic markers of lung cancer risk using multivariate analysis. Results: Median age was 48 years with 34 pack-years smoked. During 678 person-years, one lung cancer was found on incident screening. Besides this lung cancer case, 18 deaths (8%) occurred, but none were cancer related. There were no interim diagnoses of lung or extrapulmonary cancers. None of the pulmonary nodules detected in 48 participants at baseline were diagnosed as cancer by study end. The heterogeneity of emphysema across the entire lung as measured by CT densitometry was significantly higher in HIV-infected subjects with lung cancer compared with the heterogeneity of emphysema in those without HIV (p ⩽ 0.01). On multivariate regression analysis, increased age, higher smoking pack-years, low CD4 nadir, and increased heterogeneity of emphysema on quantitative CT imaging were all significantly associated with lung cancer. Conclusions: Despite a high rate of active smoking among HIV-infected participants, only one lung cancer was detected in 678 patient-years. This was probably because of the young age of participants suggesting that CT screening of high-risk populations should strongly consider advanced age as a critical inclusion criterion. Future screening trials in urban American must also incorporate robust measures to ensure HIV patient compliance, adherence, and smoking cessation.

Monitoring Daily Dynamics of Early Tumor Response to Targeted Therapy by Detecting Circulating Tumor DNA in Urine

Purpose: Noninvasive drug biomarkers for the early assessment of tumor response can enable adaptive therapeutic decision-making and proof-of-concept studies for investigational drugs. Circulating tumor DNA (ctDNA) is released into the circulation by tumor cell turnover and has been shown to be detectable in urine. Experimental Design: We tested the hypothesis that dynamic changes in EGFR activating (exon 19del and L858R) and resistance (T790M) mutation levels detected in urine could inform tumor response within days of therapy for advanced non–small cell lung cancer (NSCLC) patients receiving osimertinib, a second-line third-generation anti-EGFR tyrosine kinase inhibitor. Results: Eight of nine evaluable NSCLC patients had detectable T790M-mutant DNA fragments in pretreatment baseline samples. Daily monitoring of mutations in urine indicated a pattern of intermittent spikes throughout week 1, suggesting apoptosis with an overall decrease in fragment numbers from baselines to day 7 preceding radiographic response assessed at 6 to 12 weeks. Conclusions: These findings suggest drug-induced tumor apoptosis within days of initial dosing. Daily sampling of ctDNA may enable early assessment of patient response and proof-of-concept studies for drug development. The modeling of tumor lysis through the day-to-day kinetics of ctDNA released into the blood and then into the urine is demonstrated in this proof-of-concept study in lung cancer patients receiving anti-EGFR tyrosine kinase inhibitors. This strategy may determine the specific clonal populations of cells which undergo apoptosis within the first week of therapy. This has important implications for developing combinational strategies to address inter- and intralesional heterogeneity and characterizing residual disease after initial drug exposure. Clin Cancer Res; 23(16); 4716–23. ©2017 AACR.

Abdominal aortic aneurysms revisited: MDCT with multiplanar reconstructions for identifying indicators of instability in the pre- and postoperative patient.

Rupture of an abdominal aortic aneurysm is commonly a fatal event. Multidetector computed tomographic (CT) signs of frank aortic rupture are usually readily apparent and widely understood. However, diagnosing an impending aortic rupture on the basis of imaging findings can prove more difficult. CT is the primary modality used for serial imaging in patients with aortic aneurysm and may show findings indicative of aortic instability. Therefore, it is critical that radiologists be familiar with the CT findings of aortic instability to avert the potential complications of hemorrhage, end organ or limb ischemia, and death. Various preoperative CT indicators have been previously described in both research investigations and review articles. A large baseline aneurysm size and a rapid increase in size over time are associated with a higher risk for rupture. The importance of obtaining accurate measurements with multiplanar reconstructions and the role of new semiautomated tools for obtaining accurate, reproducible measurements are discussed. Additional CT findings that reflect aortic aneurysm instability include luminal expansion with lysis of thrombus, intramural hemorrhage (ie, the crescent sign), periaortic hemorrhage, a penetrating atherosclerotic ulcer, and contained rupture (ie, the draped aorta sign). After open or endovascular aneurysm repair, CT is routinely used to monitor for graft complications. In this setting, radiologists should understand that the presence of an endoluminal stent or surgical graft does not preclude aortic rupture. Online supplemental material is available for this article.

Exceptional Response to Nivolumab and Stereotactic Body Radiation Therapy (SBRT) in Neuroendocrine Cervical Carcinoma with High Tumor Mutational Burden: Management Considerations from the Center For Personalized Cancer Therapy at UC San Diego Moores Cancer Center

This article reports a patient with a rare metastatic, chemotherapy‐refractory neuroendocrine carcinoma who was treated with stereotactic body radiation therapy (SBRT) combined with anti‐programmed cell death protein 1 antibody. The novel treatment modality of SBRT combined with a checkpoint inhibitor is discussed, as well as the implications of molecular profiling and tumor mutational burden as potential predictors of response.

Detection of pulmonary embolism on computed tomography: improvement using a model-based iterative reconstruction algorithm compared with filtered back projection and iterative reconstruction algorithms.

Purpose: The purpose of the study was to determine whether a model-based iterative reconstruction (MBIR) technique improves diagnostic confidence and detection of pulmonary embolism (PE) compared with hybrid iterative reconstruction (HIR) and filtered back projection (FBP) reconstructions in patients undergoing computed tomography pulmonary angiography. Materials and Methods: The study was approved by our institutional review board. Fifty patients underwent computed tomography pulmonary angiography at 100 kV using standard departmental protocols. Twenty-two of 50 patients had studies positive for PE. All 50 studies were reconstructed using FBP, HIR, and MBIR. After image randomization, 5 thoracic radiologists and 2 thoracic radiology fellows graded each study on a scale of 1 (very poor) to 5 (ideal) in 4 subjective categories: diagnostic confidence, noise, pulmonary artery enhancement, and plastic appearance. Readers assessed each study for the presence of PE. Parametric and nonparametric data were analyzed with repeated measures and Friedman analysis of variance, respectively. Results: For the 154 positive studies (7 readers×22 positive studies), pooled sensitivity for detection of PE was 76% (117/154), 78.6% (121/154), and 82.5% (127/154) using FBP, HIR, and MBIR, respectively. PE detection was significantly higher using MBIR compared with FBP (P=0.016) and HIR (P=0.046). Because of nonsignificant increase in FP studies using HIR and MBIR, accuracy with MBIR (88.6%), HIR (87.1%), and FBP (87.7%) was similar. Compared with FBP, MBIR led to a significant subjective increase in diagnostic confidence, noise, and enhancement in 6/7, 6/7, and 7/7 readers, respectively. Compared with HIR, MBIR led to significant subjective increase in diagnostic confidence, noise, and enhancement in 5/7, 5/7, and 7/7 readers, respectively. MBIR led to a subjective increase in plastic appearance in all 7 readers compared with both FBP and HIR. Conclusions: MBIR led to significant increase in PE detection compared with FBP and HIR. MBIR led to qualitative improvements in diagnostic confidence, perceived noise, and perceived enhancement compared with FBP and HIR.

Radiographic Evaluation of Immunotherapy

For many radiologists, the assessment of oncology patients’ response to treatment represents a significant portion of their practice. It has been shown that radiologic responses to immunotherapy can differ from traditional cytotoxic therapy, as do the complications of treatment. Inflammatory response to immunotherapy may mimic actual progression radiologically, an entity known as pseudoprogression. As advances in immunotherapy continue, radiologists need to evolve their practice in order to be able to discern between pseudoprogression and progression. They also need to become familiar with the imaging appearance of specific immune-related adverse events, in order to accurately diagnose these complications so appropriate interventions may be expedited. This chapter will review the standardized methods of radiologically assessing tumor response to traditional cytotoxic chemotherapy as opposed to immunotherapy. It will review the entity and imaging findings of pseudoprogression, and it will also depict the radiologic findings of immune-related pneumonitis and colitis.

Radiation therapy combined with checkpoint blockade immunotherapy for metastatic undifferentiated pleomorphic sarcoma of the maxillary sinus with a complete response.

Background: Undifferentiated pleomorphic sarcoma (UPS) of the maxillary sinus is an extremely rare malignancy of the head and neck. Surgery is the mainstay of treatment for UPS; however, proximity to vital structures makes it challenging to achieve negative surgical margins. Adjuvant therapy including radiation therapy with or without chemotherapy is generally indicated. Despite advances in multimodality treatment, objective response rates to available therapies and prognosis of metastatic UPS remain dismal. Immunotherapy has become a fourth cornerstone of cancer therapy and checkpoint blockade immunotherapy is a standard of care for recurrent or metastatic cisplatin-refractory head and neck squamous cell carcinoma. Checkpoint blockade immunotherapy is being studied in metastatic sarcoma, including UPS, and while initial results are promising, objective response rates remain below 20%. However, adding radiation therapy to checkpoint blockade immunotherapy has been shown, in both preclinical and retrospective clinical studies, to have combinatorial effects on both local and metastatic disease. Thus, further investigation into the effects of radiation therapy combined with immunotherapy in head and neck sarcomas is warranted. Case Presentation: We present a case of metastatic, chemotherapy-refractory, UPS of the maxillary sinus in a 55-year-old male treated with checkpoint blockade immunotherapy combined with radiation, which resulted in a complete response. Conclusions: This is the first report to our knowledge of metastatic UPS treated with a combination of radiation and dual agent checkpoint blockade immunotherapy. Further investigation is warranted to study the effects of this combination in patients with metastatic UPS that fail to respond to currently available therapies.