Characteristics of Patients With Pulmonary Arterial Hypertension in a Pulmonary Hypertension Association-Accredited Comprehensive Care Center: A Contrast in Features When Compared With US National Registry Data.

Background Since the initial description in the 1980s, our understanding of the diversity of pulmonary arterial hypertension (PAH) has continued to evolve. In this study, we report the characteristics of patients seen in an academic medical center for PAH from August 2020 through November 2021 and contrast those with nationally reported data from the United States Pulmonary Hypertension Scientific Registry (USPHSR).  Study Design Investigators at the University of Utah Pulmonary Hypertension Program prospectively enrolled adult patients diagnosed with WHO Group 1 PAH, who were evaluated between August 2020 and November 2021 in a program-specific registry. Patient exposure and health histories were collected through structured interviews and questionnaires, along with clinical data and medication use. A total of 242 patients were enrolled in the University of Utah Pulmonary Hypertension Registry (UUPHR).  Results Of the 242 enrolled patients, the most common etiology was associated PAH (APAH), accounting for 71.1% of the population. The second largest etiology was idiopathic PAH (IPAH) at 26.4%. The remaining patients were distributed between familial PAH (FPAH), pulmonary veno-occlusive disease (PVOD), and others. Of the total population classified as APAH, 39% of cases were noted as secondary to connective tissue disease (CTD) and 33% as toxin-induced. These represented 28% and 24% of the total population, respectively.  Conclusions In this US-based accredited academic medical center, the etiology of PAH in our patient population contrasts with national registry data. In the UUPHR, APAH, specifically CTD-PAH and toxin-associated PAH, accounts for the majority of patients with PAH. This contrasts with IPAH, which nationally is the most reported cause of PAH. Differences in our population may reflect the regional variation of the referral site, but it is noteworthy for its contrast with historically reported phenotypes.

FGF21 (Fibroblast Growth Factor 21) Defines a Potential Cardiohepatic Signaling Circuit in End-Stage Heart Failure.

BACKGROUND: Extrinsic control of cardiomyocyte metabolism is poorly understood in heart failure (HF). FGF21 (Fibroblast growth factor 21), a hormonal regulator of metabolism produced mainly in the liver and adipose tissue, is a prime candidate for such signaling. METHODS: To investigate this further, we examined blood and tissue obtained from human subjects with end-stage HF with reduced ejection fraction at the time of left ventricular assist device implantation and correlated serum FGF21 levels with cardiac gene expression, immunohistochemistry, and clinical parameters. RESULTS: Circulating FGF21 levels were substantially elevated in HF with reduced ejection fraction, compared with healthy subjects (HF with reduced ejection fraction: 834.4 [95% CI, 628.4-1040.3] pg/mL, n=40; controls: 146.0 [86.3-205.7] pg/mL, n=20, P=1.9×10-5). There was clear FGF21 staining in diseased cardiomyocytes, and circulating FGF21 levels negatively correlated with the expression of cardiac genes involved in ketone metabolism, consistent with cardiac FGF21 signaling. FGF21 gene expression was very low in failing and nonfailing hearts, suggesting extracardiac production of the circulating hormone. Circulating FGF21 levels were correlated with BNP (B-type natriuretic peptide) and total bilirubin, markers of chronic cardiac and hepatic congestion. CONCLUSIONS: Circulating FGF21 levels are elevated in HF with reduced ejection fraction and appear to bind to the heart. The liver is likely the main extracardiac source. This supports a model of hepatic FGF21 communication to diseased cardiomyocytes, defining a potential cardiohepatic signaling circuit in human HF.

Burkitt Lymphoma Presenting as Perforated Appendicitis.

Appendicitis is the most common indication for an emergent abdominal operation in the pediatric population. Fewer than .015% of patients who undergo appendectomy for presumed appendicitis are diagnosed with primary lymphoma after evaluation of pathology specimen. 1 Of these primary lymphomas, 29.5% are Burkitt lymphoma. Burkitt lymphoma is an aggressive B-cell lymphoma characterized by translocation and dysregulation of the c-Myc gene. Intraabdominal extranodal Burkitt lymphoma has a polymorphic presentation that includes bowel obstruction, intussusception, and appendicitis. Here we report a case of an adolescent patient who was initially admitted for medical management of perforated appendicitis but was diagnosed with Burkitt lymphoma during his hospital course.

Stage Migration in Cervical Cancer Using the FIGO 2018 Staging System: A Retrospective Survival Analysis Using a Single-Institution Patient Cohort.

Introduction The International Federation of Gynecology and Obstetrics (FIGO) changed the staging system for cervical cancer in 2018 and formally allowed cross-sectional imaging for staging purposes. Stage IB is now divided into three substages based on tumor size (IB1 < 2 cm, IB2 2-4 cm and IB3 > 4 cm). The presence of lymph nodes in the pelvis or para-aortic region will upstage the patient to stage IIIC. The purpose of this study was to evaluate the extent of stage migration using the FIGO 2018 staging system for cervical cancer and validate the new staging system by assessing the survival outcomes. Methods An Institutional Review Board-approved and Health Insurance Portability and Accountability Act-compliant retrospective analysis was performed on 158 patients from the cervical cancer database at the University of Mississippi Medical Center, USA. Patients had been treated between January 2010 and December 2018, and they were all staged according to the FIGO 2009 staging system previously. We collected data regarding tumor size, lymph node presence, and extent of metastatic disease in the pretreatment CT, positron emission tomography (PET), or MRI scans and restaged the patients using the FIGO 2018 system. The extent of stage migration was evaluated using the new staging system. We analyzed the three-year overall survival (OS) using both FIGO 2009 and 2018 staging systems for validation purposes. Kaplan-Meier analyses were performed using SPSS version 24. Results Fifty-nine percent of the patients were upstaged when they were restaged using the FIGO 2018 staging system. In the current 2018 staging system, Stage IB3 accounted for 4%, and Stage IIIC accounted for 48% of the patient cohort, while other stages accounted for the rest. The median overall survival of the entire cohort was 20.5 months. There was a change in the survival curves using FIGO 2018 stages compared to those of FIGO 2009. There was a numerical improvement in three-year OS in stages IB and III among the two staging systems; however, it was not statistically significant. Interestingly, the three-year overall survival of Stage IIIC patients was better when compared to Stages III A& B combined (61% vs. 25%, p=0.017). Conclusion The increased availability of cross-sectional imaging across the world has led to recent changes in the FIGO staging system for cervical cancer, which allowed imaging in staging. We identified a significant stage migration in our patient cohort with the FIGO 2018 staging system, but no difference in the three-year overall survival was observed. Local tumor extent may be a worse prognostic indicator than nodal metastasis among stage III patients.

Predictors of Extracapsular Extension in Patients With Squamous Cell Carcinoma of the Head and Neck and Outcome Analysis.

Introduction Extracapsular extension (ECE) in the lymph nodes for patients with head and neck cancer has been found to be a poor prognostic factor in multiple studies. The purpose of the study is to evaluate the predictive factors for ECE on computer tomography (CT) imaging for patients undergoing surgery and to analyze outcomes. Methods We conducted an Institutional Review Board-approved, Health Insurance Portability and Accountability Act (HIPAA)-compliant retrospective review of 82 patients with biopsy-proven squamous cell carcinomas of the head and neck who underwent definitive surgery without neoadjuvant chemotherapy or radiation therapy. CT scans were evaluated for the level of involvement, size, and presence or absence of central necrosis. Extracapsular extension in lymph nodes on the postoperative pathology was correlated with the central necrosis in the lymph nodes appreciated on the CT neck with contrast. Survival estimates were evaluated using the Kaplan-Meier test. Results ECE on postoperative pathology was seen in 74.07% of patients who had evidence of central necrosis in lymph nodes on preoperative CT neck compared to 46.43% without CT necrosis (p=0.013). The incidence of ECE is higher in poorly differentiated tumors and also nodal stages >N2c at presentation. Patents with ECE had inferior disease-free and overall survival (OS). Conclusions Our results reveal that patients with necrosis on CT and with moderately to poorly differentiated tumors have a high incidence of extracapsular extension. There was no difference in local control (LC) between the groups of patients, but the OS was inferior in patients with ECE. Predicting extracapsular extension upfront helps to formulate the appropriate treatment. We propose to study additional chemotherapy to improve outcomes in patients with positive extracapsular extension.

An Analysis of the Racial Disparities Among Cervical Cancer Patients Treated at an Academic Medical Center in the Southeastern United States.

Objective The purpose of this study was to identify racial disparities in treatment outcomes, if any, among patients with carcinoma of the cervix treated at a tertiary care institution in the state of Mississippi. Methods A retrospective review of patients with carcinoma of the cervix treated in the Department of Radiation Oncology at our institution between 2010 and 2018 was performed. Data regarding demographics, disease stage, treatments administered, and follow-up were collected. Patient outcomes, including median survival and overall survival, were analyzed using the Kaplan-Meier method. All analyses were performed using SPSS Statistics version 24 (IBM, Armonk, NY). Results Between January 2010 and December 2018, a total of 165 patients with carcinoma of the cervix were treated at our institution. We had a significantly higher proportion of African American (AA) compared to Caucasian American (CA) patients (59.4 vs. 36.4%; p=0.03). There was a significant difference in the disease stage at the time of presentation between AA and CA in that compared to AA women, a higher number of CA patients presented with locally advanced disease [Federation of Gynecology and Obstetrics (FIGO) stages IB2 to IVA] (78.6 vs. 86.7%; p<0.001). However, a higher number of AA patients presented with metastatic disease at diagnosis compared to CA women (13.3 vs. 8.3%; p<0.001). Regarding their treatment, 157 (95.2%) underwent definitive chemoradiotherapy, while three (1.8%) had definitive surgery followed by adjuvant radiation or chemoradiation, depending on the risk factors identified operatively. The treatment details of five patients were not available. The median follow-up and the median survival of the entire cohort were 16 months and 79 months, respectively. In our cohort, there was no significant difference in overall survival between AA and CA patients at either three years (80 vs. 68%; p=0.883) or five years (77 vs. 68%; p=0.883). As expected, patients with locally advanced disease showed a significantly better median survival of 79 months compared to only 11 months for those with metastatic disease at their presentation (p<0.001). Conclusions Our study revealed that more AA women presented with metastatic disease compared to CA women. However, our analysis did not identify any racial disparities in the prognosis of the entire cohort.

Preventing or Minimizing Acute Kidney Injury in Patients Undergoing Transcatheter Aortic Valve Replacement.

BACKGROUND: Transcatheter aortic valve implantation (TAVI) is now routinely performed in patients with aortic stenosis with low mortality and complication rates. Although periprocedural risks have been substantially minimized, procedure- and contrast-induced acute kidney injury (AKI) remains a major concern. AKI remains a frequent complication of contrast-guided interventional procedures and is associated with a significantly adverse prognosis. We review the currently available clinical data related to AKI, with emphasis on contrast-induced nephropathy (CIN), and discuss a novel, integrated approach aiming to minimize AKI risk in high-risk patients. A stepwise algorithm is also proposed for the management of these complex patients.

Trans-Septal Puncture Through Gore® Cardioform Septal Occluder Device - Step by Step Approach.

We describe the patient selection, intraprocedural imaging, and procedural technique for transseptal puncture through the Gore® Cardioform interatrial septal occluder. Due to new indications for PFO closure and increasing need for access to the left atrium via percutaneous approach, we expect an increasing need for utilization of a trans-septal puncture technique through these devices.

A 25-year Experience at an Academic Medical Center in the United States: Are There Racial Disparities in the Prognosis of Patients Diagnosed With Hypopharyngeal Carcinoma?

Introduction This study attempted to identify disparities in outcomes between African American (AA) and Caucasian American (CA) patients treated for hypopharyngeal carcinoma at a tertiary care institution over the past 25 years. Methods An institutional review board (IRB)-approved and Health Insurance Portability and Accountability Act (HIPPA)-compliant retrospective analysis was performed on patients with squamous cell carcinoma of the hypopharynx treated at our institution between January 1994 and December 2018. Data regarding demographics, stage, treatment, and follow-up were collected. Outcomes, including median survival and overall survival, were calculated using the Kaplan-Meier method. All analyses were performed using the Social Packages for the Social Sciences (SPSS) v. 24 (IBM Corp., Armonk, NY). Results We identified 144 hypopharyngeal carcinoma patients who were treated during this period. Our patient cohort consisted of 61.8% AA and 35.4% CA (P=0.538). Overall, 96% of them presented at an advanced stage (Stages III & IV) of the disease, and only 4% presented in the early stages (Stages I & II). There was no significant difference between AA and CA patients who presented with advanced disease (96.6% vs. 94.1%). In our patient cohort, 15.3% of patients did not receive any therapy; however, 51.4%, 22.9%, and 10.4% of them underwent definitive chemoradiotherapy, definitive surgery, or palliative chemotherapy, respectively. There were no significant differences in patient racial proportions within each treatment group. The median follow-up of the entire cohort was 13 months. There was no significant difference between the median survival of AA and that of CA patients (16 months vs. 15 months; p=0.917). Moreover, there was no significant difference in the overall survival between AA and CA patients at three years (27.2% vs. 36.3%; p=0.917) and five years (20.4 % vs. 16.7 %; p=0.917). Conclusions A retrospective review of patients with hypopharyngeal cancer treated at our institution over the previous 25 years did not identify significant racial disparities regarding the stage at presentation or prognosis. This study suggests that when patients have equal access to care, they appear to have a similar prognosis despite racial differences. Further studies are needed to validate this hypothesis.

Oligometastatic head and neck cancer: Comprehensive review.

There are limited data available regarding the management of oligometastatic squamous cell carcinoma of the head and neck (SCCHN) patients, and no consensus guidelines are available. The objective is to review the available literature for the management of oligometastatic SCCHN. Articles were selected from English Medline literature between 1995 and 2018, searched by using the keywords: oligometastatic SCCHN/metastasectomy/stereotactic body radiation treatment (SBRT). With the available data, oligometastatic SCCHN patients appear to behave differently and tend to have a better prognosis than those with widespread metastases. Retrospective evidence suggests that the aggressive treatment of the primary disease and local treatment of the metastatic sites improves survival in oligometastatic SCCHN at diagnosis. The definitive treatment of the distant metastatic sites using metastasectomy or SBRT correlates with better survival in oligorecurrent patients. Oligometastatic SCCHN patients may have a better prognosis if treated aggressively.

BCR-ABL1-like B-Acute Lymphoblastic Leukemia/Lymphoma: A Comprehensive Review.

CONTEXT.­: In the 2016 update of the World Health Organization (WHO) classification of hematopoietic neoplasms, BCR-ABL1-like B-acute lymphoblastic leukemia/lymphoma (B-ALL) is added as a new provisional entity that lacks the BCR-ABL1 translocation but shows a pattern of gene expression very similar to that seen in B-ALL with BCR-ABL1. OBJECTIVE.­: To review the kinase-activating alterations and the diagnostic approach for BCR-ABL1-like B-ALL. DATA SOURCES.­: We provide a comprehensive review of BCR-ABL1-like B-ALL based on recent literature and the 2016 update of the World Health Organization classification of hematopoietic neoplasms. CONCLUSIONS.­: Several types of kinase-activating alterations (fusions or mutations) are identified in BCR-ABL1-like B-ALL. The main categories are alterations in the ABL class family of genes, encompassing ABL1, ABL2, PDGFRB, PDGFRA (rare), and colony-stimulating factor 1 receptor (CSF1R) fusions, or the JAK2 class family of genes, encompassing alterations in JAK2, CRLF2, EPOR, and other genes in this pathway. These alterations determine the sensitivity to tyrosine kinase inhibitors. As a wide variety of genomic alterations are included in this category, the diagnosis of BCR-ABL1-like B-ALL is extremely complex. Stepwise algorithms and comprehensive unbiased testing are the 2 ways to approach the diagnosis of BCR-ABL1-like B-ALL.

Malignant peripheral nerve sheath tumor of nasal cavity and paranasal sinus with 13 years of follow-up-A case report and review of literature.

Although extremely rare, sarcomas including malignant peripheral nerve sheath tumors should be considered in the differential diagnosis of sino-nasal tract lesions. Long-term cure is possible through definitive operative management followed by adjuvant therapy.

Strong Relationship Between Vascular Function in the Coronary and Brachial Arteries.

Early detection of coronary artery dysfunction is of paramount cardiovascular clinical importance, but a noninvasive assessment is lacking. Indeed, the brachial artery flow-mediated dilation test only weakly correlated with acetylcholine-induced coronary artery function ( r=0.36). However, brachial artery flow-mediated dilation methodologies have, over time, substantially improved. This study sought to determine if updates to this technique have improved the relationship with coronary artery function and the noninvasive indication of coronary artery dysfunction. Coronary artery and brachial artery function were assessed in 28 patients referred for cardiac catheterization (61±11 years). Coronary artery function was determined by the change in artery diameter with a 1.82 µg/min intracoronary acetylcholine infusion. Based on the change in vessel diameter, patients were characterized as having dysfunctional coronary arteries (>5% vasoconstriction) or relatively functional coronary arteries (<5% vasoconstriction). Brachial artery function was determined by flow-mediated dilation, adhering to current guidelines. The acetylcholine-induced change in vessel diameter was smaller in patients with dysfunctional compared with relatively functional coronary arteries (-11.8±4.6% versus 5.8±9.8%, P<0.001). Consistent with this, brachial artery flow-mediated dilation was attenuated in patients with dysfunctional compared with relatively functional coronaries (2.9±1.9% versus 6.2±4.2%, P=0.007). Brachial artery flow-mediated dilation was strongly correlated with the acetylcholine-induced change in coronary artery diameter ( r=0.77, P<0.0001) and was a strong indicator of coronary artery dysfunction (receiver operator characteristic=78%). The current data support that updates to the brachial artery flow-mediated dilation technique have strengthened the relationship with coronary artery function, which may now provide a clinically meaningful indication of coronary artery dysfunction.

Management strategies and possible risk factors for ventricular septal defects after transcatheter aortic valve replacement: Case series from a single center and review of literature.

Development of membranous ventricular septal defects (VSD) is a rare complication of transcatheter aortic valve replacements (TAVR), and is recognized using intraoperative and postoperative imaging. We present two cases of this rare but serious complication; one was successfully managed conservatively and the other with valve-in-valve therapy. Management strategies for post-TAVR VSDs varies, but should be individualized to the clinical scenario. We performed a literature search and sought to identify various risk factors which may predispose patients to the development of VSD after TAVR.

Mesenchymal Stem/Stromal Cells under Stress Increase Osteosarcoma Migration and Apoptosis Resistance via Extracellular Vesicle Mediated Communication.

Studies have shown that mesenchymal stem/stromal cells (MSCs) from bone marrow are involved in the growth and metastasis of solid tumors but the mechanism remains unclear in osteosarcoma (OS). Previous studies have raised the possibility that OS cells may receive support from associated MSCs in the nutrient deprived core of the tumors through the release of supportive macromolecules and growth factors either in vesicular or non-vesicular forms. In the present study, we used stressed mesenchymal stem cells (SD-MSCs), control MSCs and OS cells to examine the hypothesis that tumor-associated MSCs in nutrient deprived core provide pro-proliferative, anti-apoptotic, and metastatic support to nearby tumor cells. Assays to study of the effects of SD-MSC conditioned media revealed that OS cells maintained proliferation when compared to OS cells grown under serum-starved conditions alone. Furthermore, OS cells in MSCs and SD-MSC conditioned media were significantly resistant to apoptosis and an increased wound healing rate was observed in cells exposed to either conditioned media or EVs from MSCs and SD-MSCs. RT-PCR assays of OS cells incubated with extracellular vesicles (EVs) from SD-MSCs revealed microRNAs that could potentially target metabolism and metastasis associated genes as predicted by in silico algorithms, including monocarboxylate transporters, bone morphogenic receptor type 2, fibroblast growth factor 7, matrix metalloproteinase-1, and focal adhesion kinase-1. Changes in the expression levels of focal adhesion kinase, STK11 were confirmed by quantitative PCR assays. Together, these data indicate a tumor supportive role of MSCs in osteosarcoma growth that is strongly associated with the miRNA content of the EVs released from MSCs under conditions that mimic the nutrient deprived core of solid tumors.

A prospective observational study of early fetal growth velocity and its association with birth weight, gestational age at delivery, preeclampsia, and perinatal mortality.

OBJECTIVES: We aimed to measure early fetal growth velocity and to correlate this with the birth weight, gestational age at delivery, and with the incidence of adverse pregnancy outcomes specifically preeclampsia and perinatal mortality. METHODS: A data based prospective observational study, wherein sonographic biometry data and specific pregnancy outcome related data were collected from pregnant women's records, starting soon after their first antenatal visit. Early fetal growth velocity was measured using BPD growth between 11 and 14 weeks scan and anomaly scan and standardizing this by Z scoring. RESULTS: Out of 607 fetuses, 41 (6.7%) were slow growing, 531 (87.4%) normally growing, and 35 (5.7%) fast growing (Z scoring <10th(,) 10-90th, and >90th percentiles respectively). As fetal growth velocity increased, the mean birth weight decreased from 2958.7±388.9 (<10th centile), 2742.1±576.6 (10-90th centile), to 2339.3±729.4 (>90th centile); and gestational age at delivery decreased from 38.5±1.3 (<10th centile), 37.5±2.1 (10-90th centile), to 36.4±2.2 (>90th centile), and both these trends were statistically significant (p<0.001).Faster growing fetuses had a higher risk of preterm delivery(spontaneous+indicated) compared to other 2 groups [OR 4.42 (2.18,8.98)], and slower growing fetuses had a higher risk of postdated deliveries compared to other 2 groups [OR 3.042 (1.44, 6.45)].We found no significant association between early fetal growth velocity and incidence of small for gestational age at birth/low birth weight at term, preeclampsia, and perinatal mortality. CONCLUSIONS: Early fetal growth velocity between first and second trimesters, may be one of the important factors influencing ultimate birthweight and gestational age at delivery.

Correlations between 31P chemical shift anisotropy and molecular structure in polycrystalline O,O'-dialkyldithiophosphate zinc(II) and nickel(II) complexes: 31P CP/MAS NMR and ab initio quantum mechanical calculation studies.

Different potassium salts and zinc(II) and nickel(II) O,O'-dialkyldithiophosphate complexes were studied by solid-state 31P CP/MAS and static NMR and ab initio quantum mechanical calculations. Spectra were obtained at different spinning frequencies, and the intensities of the spinning sidebands were used to estimate the chemical shift anisotropy parameters. Useful correlations between the shapes of the 31P chemical shift tensor and the type of ligand were found: terminal ligands have negative values of the skew kappa, while bridging and ionic ligands have positive values for this parameter. The experimental results were compared with known X-ray diffraction structures for some of these complexes as well as with ab initio quantum mechanical calculations, and a useful correlation between the delta22 component of the 31P chemical shift tensor and the S-P-S bond angle in the O,O'-dialkyldithiophoshate zinc(II) and nickel(II) complexes was found: delta22 increases more than 50 ppm with the increase of S-P-S bond angle from ca. 100 degrees to 120 degrees , while the other two principal values of the tensor, delta11 and delta33, are almost conserved. This eventually leads to the change in sign for kappa in the bridging type of ligand, which generally has a larger S-P-S bond angle than the terminally bound O,O'-dialkyldithiophosphate group forming chelating four-membered P(ss)Me heterocycles.