The genomic trajectory of ovarian high-grade serous carcinoma can be observed in STIC lesions.

Ovarian high-grade serous carcinoma (HGSC) originates in the fallopian tube, with secretory cells carrying a TP53 mutation, known as p53 signatures, identified as potential precursors. p53 signatures evolve into serous tubal intraepithelial carcinoma (STIC) lesions, which in turn progress into invasive HGSC, which readily spreads to the ovary and disseminates around the peritoneal cavity. We recently investigated the genomic landscape of early- and late-stage HGSC and found higher ploidy in late-stage (median 3.1) than early-stage (median 2.0) samples. Here, to explore whether the high ploidy and possible whole-genome duplication (WGD) observed in late-stage disease were determined early in the evolution of HGSC, we analysed archival formalin-fixed paraffin-embedded (FFPE) samples from five HGSC patients. p53 signatures and STIC lesions were laser-capture microdissected and sequenced using shallow whole-genome sequencing (sWGS), while invasive ovarian/fallopian tube and metastatic carcinoma samples underwent macrodissection and were profiled using both sWGS and targeted next-generation sequencing. Results showed highly similar patterns of global copy number change between STIC lesions and invasive carcinoma samples within each patient. Ploidy changes were evident in STIC lesions, but not p53 signatures, and there was a strong correlation between ploidy in STIC lesions and invasive ovarian/fallopian tube and metastatic samples in each patient. The reconstruction of sample phylogeny for each patient from relative copy number indicated that high ploidy, when present, occurred early in the evolution of HGSC, which was further validated by copy number signatures in ovarian and metastatic tumours. These findings suggest that aberrant ploidy, suggestive of WGD, arises early in HGSC and is detected in STIC lesions, implying that the trajectory of HGSC may be determined at the earliest stages of tumour development. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

In vitro activity of cefiderocol against carbapenem-resistant Acinetobacter baumannii carrying various ß-lactamase encoding genes.

OBJECTIVES: This study aimed to determine the in vitro efficacy of cefiderocol in carbapenem-resistant Acinetobacter baumannii (CRAB) isolates and evaluate the disk-diffusion (DD) method as an alternative method to broth-microdilution (BMD). METHODS: Totally 89 CRAB isolates were included. Cluster analysis was determined by Pulsed-Field Gel Electrophoresis (PFGE). Resistance genes; blaOXA-51, blaOXA-23, blaOXA-24, blaOXA-58,blaPER-1, blaNDM, blaIMP and mcr-1 were screened. Cefiderocol susceptibility testing was performed by both DD and BMD. Interpretation was made according to EUCAST and CLSI. Categorical agreement (CA), minor errors (mEs), major errors (MEs), and very major errors (VMEs) were determined. RESULTS: PFGE revealed 5 distinct pulsotypes; 86 of the isolates were extensively drug-resistant (XDR). All the isolates were negative for blaNDM, blaIMP, mcr-1, while positive for blaOXA-58 and blaOXA51. blaPER-1 was positive for 33.7%; blaOXA-23 for 74.2%; blaOXA-24 for 12.3%. According to CLSI, the MEs rate was 1.85%, mEs was 7.86% and there were no VMEs. According to EUCAST, MEs rate was 3.70%, there were no mEs and VMEs. CA was 91% for CLSI and 97.8% for EUCAST. MICs of cefiderocol against A. baumannii isolates ranged from 0.06 to > 128 mg/L, with MIC50 and MIC90 values of 0.5 and > 128 mg/L, respectively. CONCLUSIONS: Cefiderocol susceptibility was 60.7% in CRAB isolates. MIC50, MIC90 of blaPER-1 positive and blaPER-1 negative groups were > 128/>128 and 0.25/>128 mg/L. A correlation between the presence of blaPER-1 and cefiderocol resistance was observed (p < 0.0001). Among colistin-resistant isolates, the presence of blaPER-1 was 47.1% and 75% of them were resistant to cefiderocol respectively.

Evaluation of the Lytic Activity of Various Phage Cocktails Against, ESBL-Producer, Non-Producer and Carbapenem-Resistant Escherichia coli Isolates.

Bacteriophages have been proposed as an alternative therapy for the treatment of bacterial infections. This research aims to determine the lytic activity of bacteriophage-cocktails (BC) against carbapenem-resistant (CR-EC), ESBL-producer (EP-EC), and non-producer (NP-EC) E. coli isolates. Related resistance genes in 87 E. coli isolates were screened by PCR. The efficacies of BCs were determined by spot test and lytic zones were evaluated from fully-confluent to opaque. MOIs of the BCs were compared for fully-confluent and opaque lytic zones. BCs were also evaluated in terms of their biophysical characteristics including latency, burst size, pH and temperature stabilities. Among EP-EC, 96.9% of the isolates carry blaCTX-M, 25% of them blaSHV and 15.6% of them carry blaTEM. All CR-EC isolates carried blaOXA-48, but not blaKPC and blaNDM. CR-EC isolates were the least susceptible for the each of four BCs. MOIs for ENKO, SES and INTESTI-phage forming fully-confluent zone in E. coli isolates EC3 (NP-EC), EC8 (EP-EC) and EC27 (NP-EC), respectively were 10, 100 and 1, respectively. MOIs for ENKO, SES and INTESTI opaque zone in EC19 (EP-EC), EC10 (EP-EC), EC1(NP-EC), respectively were 0.01, 0.01, 0.1 PFU/CFU, respectively. The MOI for PYO-phage forming a semi-confluent zone in EC6 (NP-EC) isolate was 1 PFU/CFU. The phages were thermally stable and tolerant to a wide pH range. Comparison of MOIs according to lysis zone characteristics demonstrated that the activities of phages in phage cocktails vary depending on the characteristics of each bacterial host. Supplementary Information: The online version contains supplementary material available at 10.1007/s12088-023-01074-9.

Comparison of in vitro activities of plazomicin and other aminoglycosides against clinical isolates of Klebsiella pneumoniae and Escherichia coli.

OBJECTIVES: To compare the in vitro activity of plazomicin and two older aminoglycosides (gentamicin and amikacin) against 180 isolates of Escherichia coli and Klebsiella pneumoniae, including subsets of 60 non-ESBL-producing, 60 ESBL-producing and 60 carbapenem-resistant (46 carrying blaOXA-48, 11 carrying blaNDM and 3 carrying blaOXA-48 and blaNDM) strains. METHODS: MICs of plazomicin, gentamicin and amikacin were determined by a gradient diffusion method. Gentamicin and amikacin MICs were interpreted according to CLSI criteria and EUCAST breakpoint tables. Plazomicin MICs were interpreted using FDA-defined breakpoints. RESULTS: All non-ESBL-producing and ESBL-producing isolates were susceptible to plazomicin. The plazomicin susceptibility rate (71.7%) in carbapenem-resistant isolates was significantly higher than those observed for gentamicin (45%) and amikacin (56.7% and 51.7% according to CLSI and EUCAST breakpoints, respectively). Gentamicin, amikacin and plazomicin susceptibility rates (35.6% for gentamicin; 44.4% and 37.8% for amikacin according to CLSI and EUCAST breakpoints, respectively; 64.4% for plazomicin) in carbapenem-resistant K. pneumoniae were significantly lower than those observed for carbapenem-resistant E. coli isolates (73.3% for gentamicin; 93.3% for amikacin and plazomicin). Gentamicin, amikacin and plazomicin susceptibility rates for blaNDM-positive isolates were lower than those observed for blaOXA-48-positive isolates, but differences were not statistically significant. Among the isolates that were non-susceptible to both gentamicin and amikacin, the plazomicin susceptibility rate was less than 30%. CONCLUSIONS: Although plazomicin showed excellent in vitro activity against carbapenem-susceptible isolates, the plazomicin resistance rate increased to 35.6% among carbapenem-resistant K. pneumoniae and further increased to 45.5% among blaNDM-positive isolates.

Evaluation of a Commercial Broth Microdilution Panel for Colistin Susceptibility Testing of Clinical Isolates of Escherichia coli and Klebsiella pneumoniae.

BACKGROUND: Colistin is among the last resort antibiotics for the treatment of infections caused by multidrug-resistant Gram-negative pathogens. Antimicrobial susceptibility testing of colistin is challenging due to its physicochemical properties. Broth microdilution (BMD) is the recommended method for colistin susceptibility testing. However BMD is not practical for clinical microbiology laboratories as manual preparation of BMD plates is time-consuming and labor intensive. Recently, some more user-friendly BMD products with commercial panels have become available. Our objective was to evaluate the performance of a commercial broth microdilution (BMD) product [Sensititre (Thermo Fisher Scientific)] for colistin MIC determination by comparison with reference BMD method using a collection of E. coli and K. pneumoniae isolates. METHODS: A total of 323 unique patient isolates (102 E. coli, 221 K. pneumoniae) were included in the study. Isolates were stored at -70°C and subcultured twice on sheep blood agar before testing. Colistin MICs of the isolates were determined using Sensititre (a premade BMD product with dried antibiotics) and an 'in-house prepared BMD panel prepared in accordance with CLSI guidelines' (reference method). MIC determination with Sensititre was performed according to manufacturer's instructions. The reference method was performed using untreated 96-well sterile polystyrene plates. Colistin MIC results were interpreted according to EUCAST breakpoints (susceptible, ≤ 2 mg/L; resistant, > 2 mg/L). RESULTS: Overall susceptibility rate of isolates to colistin by reference BMD was 75.9%. Overall categorical agreement (CA), essential agreement (EA), very major error (VME), and major error (ME) rates for Sensititre were 98.5%, 72.5%, 3.8%, and 0.8%, respectively. The CA and EA between Sensititre and reference BMD for the isolates with reference colistin MICs close to the susceptibility breakpoint (2 - 8 mg/L) was 94.2% and 48.1%, respectively. Sensititre yielded a VME rate of 15% and ME rate of 0%, respectively, for this subset of isolates. CONCLUSIONS: In conclusion, Sensititre showed high CA but low EA with reference BMD for entire collection of isolates. The VME rate was just slightly above 3% and ME rate was acceptable. The rates of CA and EA were decreased and the rate of VME was increased when a subset consisting of more challenging isolates was used.

Functional and prognostic significance of the genomic amplification of frizzled 6 (FZD6) in breast cancer.

Frizzled receptors mediate Wnt ligand signalling, which is crucially involved in regulating tissue development and differentiation, and is often deregulated in cancer. In this study, we found that the gene encoding the Wnt receptor frizzled 6 (FZD6) is frequently amplified in breast cancer, with an increased incidence in the triple-negative breast cancer (TNBC) subtype. Ablation of FZD6 expression in mammary cancer cell lines: (1) inhibited motility and invasion; (2) induced a more symmetrical shape of organoid three-dimensional cultures; and (3) inhibited bone and liver metastasis in vivo. Mechanistically, FZD6 signalling is required for the assembly of the fibronectin matrix, interfering with the organization of the actin cytoskeleton. Ectopic delivery of fibronectin in FZD6-depleted, triple-negative MDA-MB-231 cells rearranged the actin cytoskeleton and restored epidermal growth factor-mediated invasion. In patients with localized, lymph node-negative (early) breast cancer, positivity of tumour cells for FZD6 protein identified patients with reduced distant relapse-free survival. Multivariate analysis indicated an independent prognostic significance of FZD6 expression in TNBC tumours, predicting distant, but not local, relapse. We conclude that the FZD6-fibronectin actin axis identified in our study could be exploited for drug development in highly metastatic forms of breast cancer, such as TNBC. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Selection and evolution in the genomic landscape of copy number alterations in ductal carcinoma in situ (DCIS) and its progression to invasive carcinoma of ductal/no special type: a meta-analysis.

Ductal carcinoma in situ (DCIS) is a pre-invasive malignancy detected with an increasing frequency through screening mammography. One of the primary aims of therapy is to prevent local recurrence, as in situ or as invasive carcinoma, the latter arising in half of the recurrent cases. Reliable biomarkers predictive of its association with recurrence, particularly as invasive disease, are however lacking. In this study, we perform a meta-analysis of 26 studies which report somatic copy number aberrations (SCNAs) in 288 cases of 'pure' DCIS and 328 of DCIS associated with invasive carcinoma, along with additional unmatched cases of 145 invasive carcinoma of ductal/no special type (IDC) and 50 of atypical ductal hyperplasia (ADH). SCNA frequencies across the genome were calculated at cytoband resolution (UCSC genome build 19) to maximally utilize the available information in published literature. Fisher's exact test was used to identify significant differences in the gain-loss distribution in each cytoband in different group comparisons. We found synchronous DCIS to be at a more advanced stage of genetic aberrations than pure DCIS and was very similar to IDC. Differences in gains and losses in each disease process (i.e. invasive or in situ) at each cytoband were used to infer evidence of selection and conservation for each cytoband and to define an evolutionary conservation scale (ECS) as a tool to identify and distinguish driver SCNA from the passenger SCNA. Using ECS, we have identified aberrations that show evidence of selection from the early stages of neoplasia (i.e. in ADH and pure DCIS) and persist in IDC; we postulate these to be driver aberrations and that their presence may predict progression to invasive disease.

Evaluation of in vitro activity of ceftaroline, ceftobiprole and their combination with trimethoprim/sulfamethoxazole against MRSA isolates: a two center study.

There is an increasing need for new synergistic antimicrobial combinations against multidrug-resistant bacteria. Our objective was to evaluate the activity of ceftaroline, ceftobiprole and their combination with trimethoprim/sulfamethoxazole against methicillin-resistant Staphylococcus aureus (MRSA) isolates recovered at two centers in Turkey. Activities of ceftaroline and ceftobiprole were tested against 100 MRSA isolates using gradient diffusion method. Activities of ceftaroline and ceftobiprole in combination with trimethoprim/sulfamethoxazole against 20 selected isolates (including all isolates that were non-susceptible to ceftaroline or ceftobiprole, and randomly selected isolates) were investigated using MIC:MIC ratio method. Antimicrobial interactions were interpreted using the fractional inhibitory concentration (FIC) index. The MIC50/MIC90 values for ceftaroline and ceftobiprole were 0.75/1 and 1/1.5 mg/L, respectively. Ceftaroline and ceftobiprole susceptibility rates among 100 MRSA isolates were 94% and 96%, respectively. Ceftaroline, ceftobiprole and trimethoprim/sulfamethoxazole MICs of isolates were not increased when ceftaroline or ceftobiprole was combined with trimethoprim/sulfamethoxazole. Ceftobiprole- trimethoprim/sulfamethoxazole combination demonstrated additivity against 35%, whereas ceftaroline- trimethoprim/sulfamethoxazole combination demonstrated additivity against 10% of 20 MRSA isolates. The remaining interactions for MRSA isolates were indifference. Three (75%) of four ceftobiprole-resistant isolates became susceptible to ceftobiprole after adding trimethoprim/sulfamethoxazole. None of the ceftaroline non-susceptible isolates became susceptible to ceftaroline after adding trimethoprim/sulfamethoxazole. Ceftobiprole- trimethoprim/sulfamethoxazole combination may be a better treatment option than ceftaroline- trimethoprim/sulfamethoxazole combination for MRSA infections. Clinical studies are needed to confirm the results of our in vitro study.

Spontaneous coronary artery dissection (SCAD) and takotsubo cardiomyopathy (TCM) - A potential association.

Background: Spontaneous coronary artery dissection and takotsubo cardiomyopathy are increasingly recognized in the last two decades. Case reports have shown both entities can present concomitantly - however, little is known about their association. Methods: In this retrospective study we aimed to explore a potential association between SCAD and TCM using the Nationwide Inpatient Sample. The odds of having TCM among patients with SCAD compared with those who did not have SCAD were calculated as an odds ratio. Conversely, the odds of having SCAD among patients with TCM compared with those who did not have TCM were also calculated. The primary outcome was the odds of TCM among patients with a primary diagnosis of SCAD and vice versa. The secondary endpoint was the odds of in-hospital mortality among patients with SCAD, and/or TCM. Results: Hospitalized patients who had SCAD were 7.12 (95 % CI: 6.28-8.08) times more likely to also have TCM than those who did not have SCAD (p < 0.0001).), while patients with TCM were 6.91 (95 % CI: 6.07-7.85) times more likely to have SCAD compared to those who didn't have TCM adjusted for age, gender, race, hypertension, hyperlipidemia, and diabetes mellitus (p < 0.0001). Conclusion: This data indicate that patients with either SCAD or TCM are seven times more likely to be diagnosed concomitantly with both, compared to the patients without either diagnosis [after adjusting for age, gender, race, hypertension, hyperlipidemia, and diabetes mellitus]. Our data are consistent with the growing body of evidence supporting an association between SCAD and TCM and raise the question of a common pathophysiologic mechanism.

Efficacy and Safety of Weekly Paclitaxel Plus Vistusertib vs Paclitaxel Alone in Patients With Platinum-Resistant Ovarian High-Grade Serous Carcinoma: The OCTOPUS Multicenter, Phase 2, Randomized Clinical Trial.

Importance: Patients with platinum-resistant or refractory ovarian high-grade serous carcinoma (PR-HGSC) have a poor prognosis and few therapeutic options. Preclinical studies support targeting PI3K/AKT/mTOR signaling in this setting, and a phase 1 study of the dual mTORC1/mTORC2 inhibitor vistusertib with weekly paclitaxel showed activity. Objective: To evaluate whether the addition of vistusertib to weekly paclitaxel improves clinical outcomes in patients with PR-HGSC. Design, Setting, and Participants: This phase 2, double-blind, placebo-controlled multicenter randomized clinical trial recruited patients from UK cancer centers between January 2016 and March 2018. Patients with PR-HGSC of ovarian, fallopian tube, or primary peritoneal origin and with measurable or evaluable disease (Response Evaluation Criteria in Solid Tumors version 1.1 and/or Gynecological Cancer Intergroup cancer antigen 125 criteria) were eligible. There were no restrictions on number of lines of prior therapy. Data analysis was performed from May 2019 to January 2022. Interventions: Patients were randomized (1:1) to weekly paclitaxel (80 mg/m2 days 1, 8, and 15 of a 28-day cycle) plus oral vistusertib (50 mg twice daily) or placebo. Main Outcomes and Measures: The primary end point was progression-free survival in the intention-to-treat population. Secondary end points included response rate, overall survival, and quality of life. Results: A total of 140 patients (median [range] age, 63 [36-86] years; 17.9% with platinum-refractory disease; 53.6% with ≥3 prior therapies) were randomized. In the paclitaxel plus vistusertib vs paclitaxel plus placebo groups, there was no difference in progression-free survival (median, 4.5 vs 4.1 months; hazard ratio [HR], 0.84; 80% CI, 0.67-1.07; 1-sided P = .18), overall survival (median, 9.7 vs 11.1 months; HR, 1.21; 80% CI, 0.91-1.60) or response rate (odds ratio, 0.86; 80% CI, 0.55-1.36). Grade 3 to 4 adverse events were 41.2% (weekly paclitaxel plus vistusertib) vs 36.7% (weekly paclitaxel plus placebo), and there was no difference in quality of life. Conclusions and Relevance: In this randomized clinical trial of weekly paclitaxel and dual mTORC1/2 inhibition in patients with PR-HGSC, vistusertib did not improve clinical activity of weekly paclitaxel. Trial Registration: isrctn.org Identifier: ISRCTN16426935.

The copy number and mutational landscape of recurrent ovarian high-grade serous carcinoma.

The drivers of recurrence and resistance in ovarian high grade serous carcinoma remain unclear. We investigate the acquisition of resistance by collecting tumour biopsies from a cohort of 276 women with relapsed ovarian high grade serous carcinoma in the BriTROC-1 study. Panel sequencing shows close concordance between diagnosis and relapse, with only four discordant cases. There is also very strong concordance in copy number between diagnosis and relapse, with no significant difference in purity, ploidy or focal somatic copy number alterations, even when stratified by platinum sensitivity or prior chemotherapy lines. Copy number signatures are strongly correlated with immune cell infiltration, whilst diagnosis samples from patients with primary platinum resistance have increased rates of CCNE1 and KRAS amplification and copy number signature 1 exposure. Our data show that the ovarian high grade serous carcinoma genome is remarkably stable between diagnosis and relapse and acquired chemotherapy resistance does not select for common copy number drivers.

Comparative in vitro activities of omadacycline, eravacycline and tigecycline against non-ESBL-producing, ESBL-producing and carbapenem-resistant isolates of K. pneumoniae.

Introduction. Extended-spectrum ß-lactamase (ESBL)-producing Enterobacteriaceae and carbapenem-resistant Enterobacteriaceae are characterized by the World Health Organization as pathogens for which new antibiotics are urgently needed. Omadacycline and eravacycline are two novel antibacterials within the tetracycline class.Gap Statement. There are limited data regarding the comparison of the activities of omadacycline, eravacycline and tigecycline against K. pneumoniae isolates with different antimicrobial susceptibility profiles.Aim. Our objective was to compare the in vitro activities of omadacycline, eravacycline and tigecycline against a collection of K. pneumoniae isolates, including non-ESBL-producing, ESBL-producing and carbapenem-resistant strains.Methodology. Ninety-four K. pneumoniae isolates, including 30 non-ESBL-producing, 30 ESBL-producing and 34 carbapenem-resistant (22 carrying bla OXA-48, 12 carrying bla NDM) strains were included in the study. ESBL and carbapenemase genes were detected by conventional PCR. Omadacycline, eravacycline and tigecycline MICs were determined by the gradient diffusion method and interpreted using US Food and Drug Administration (FDA)-defined breakpoints.Results. Overall, the percentage of tigecycline-susceptible strains (97.9 %) was higher than the percentage of omadacyline-susceptible (75.5 %) and eravacycline-susceptible (72.3 %) strains. The omadacycline and eravacycline susceptibility rates were 83.3 % among non-ESBL-producing isolates and 66.7 % among ESBL-producing isolates. The most common ESBL gene detected was blaCTX -M (90 %), followed by bla TEM (50 %) and bla SHV (50 %). The omadacycline and eravacycline susceptibility rate among isolates carrying bla TEM was 33.3 %, whereas it was 100 % among isolates that do not carry bla TEM. The omadacycline and eravacycline susceptibility rates among carbapenem-resistant isolates were 76.5 and 67.6 %, respectively. The omadacycline susceptibility rates among bla OXA-48-positive and bla NDM-positive isolates were 77.3 and 75.0 %, respectively. The eravacycline susceptibility rates among bla OXA-48-positive and bla NDM-positive isolates were 68.2 and 66.7 %, respectively. One carbapenem-resistant isolate was intermediate and one ESBL-producing isolate was resistant to tigecycline.Conclusion. Overall, tigecycline was the most active tetracycline against isolates. Omadacycline and eravacycline showed excellent activity against ESBL-producing K. pneumoniae isolates that do not carry bla TEM. Omadacycline showed reasonable activity against carbapenem-resistant K. pneumoniae isolates carrying bla OXA-48 or bla NDM.

Contemporary trends in the incidence of spontaneous coronary artery dissection (SCAD) - ethnic and household income disparities.

OBJECTIVES: Spontaneous coronary artery dissection (SCAD) may contribute to 35% of acute coronary syndrome among women ≤50 years of age. We aimed to investigate the overall incidence, as well as the trends of SCAD incidence based on race, household income, and the U.S. census regions utilizing the National Inpatient Sample. METHODS: In this retrospective cohort study the discharge data were extracted from the NIS using 9th and 10th revisions of the International Classification Disease for SCAD. RESULTS: We found that the incidence of SCAD is rising in all U.S. census regions, and patients were predominantly females. Overall crude incidence of SCAD per 1,000,000 discharges per year was found to be 4.95 (2010), 5.73 (2011), 5.34 (2012), 6.18 (2013), 7.64 (2014), 8.11 (2015), 14.58 (2016), and 14.81 (2017). There was a higher incidence of SCAD in white population and higher-income groups. Among U.S. census regions, West has had the highest incidence followed by the Northeast, Midwest, and South. Statistically significant differences were observed in year-to-year SCAD incidence among racial groups, household income quintiles, and U.S. census regions (P < 0.0001). CONCLUSION: Recent trends indicate that the incidence is highest among White race, highest household income quintile, and in U.S. CENS-R4 (Census Region 4: West). These findings defy classic racial trends in cardiovascular disease burden which need further discovery.

A Review of Left Ventricular Non-compaction Cardiomyopathy (LVNC).

Left ventricular non-compaction (LVNC) is a rare congenital phenotype defined by the presence of prominent left ventricular trabeculae, deep intertrabecular recesses (continuous with the ventricular cavity), and a thin compacted layer. The most common presentation of LVNC is dyspnea (60%), followed by palpitations (18%), chest pain (15%), syncope (9%), and prior stroke (3%). LVNC presenting with acute myocardial infarction (MI) has rarely been reported in the literature. A forty-one-years old female presented with substernal chest pain and exertional dyspnea. On physical examination, she was alert without any distress, her lungs and heart examination were within normal limits. Peripheral pulses were palpable and regular, and +1 peripheral pitting edema was noted. EKG showed normal sinus rhythm with premature atrial contractions (PACs), left axis deviation, and ST-segment and T wave changes suggestive of inferior wall ischemia. Troponin I level was found to be elevated, which peaked within 24 hours, Troponinmax 110.08 ng/ml. Transthoracic echocardiography showed moderate LV dilatation with severely reduced EF (15-20%), and diffuse LV hypokinesis with a grade III restrictive pattern. There was heavy trabeculation of LV involving 2/3rd LV endocardium and wall thickness with sinusoidal tunnels perpendicular to LV wall. These morphological findings met the diagnostic criteria of LVNC/NCM. LVNC presenting with acute myocardial infarction (MI) can be related to poor outcomes, however, more data is needed to establish the clinical implication of this presentation. Asymptomatic LVNC can be observed while symptomatic LVNC should be treated with standard guidelines of HF.

Hypertension as an Independent Risk Factor for In-Patient Mortality in Hospitalized COVID-19 Patients: A Multicenter Study.

Despite the lack of direct evidence that hypertension increases the likelihood of new infections, hypertension is known to be the most common comorbid condition in COVID-19 patients and also a major risk factor for severe COVID-19 infection. The literature review suggests that data is heterogeneous in terms of the association of hypertension with mortality. Hence, it remains a topic of interest whether hypertension is associated with COVID-19 disease severity and mortality. Herein, we perform a multicenter retrospective analysis to study hypertension as an independent risk for in-hospital mortality in hospitalized COVID-19 patients. This multicenter retrospective analysis included 515 COVID-19 patients hospitalized from March 1, 2020 to May 31, 2020. Patients were divided into two groups: hypertensive and normotensive. Demographic characteristics and laboratory data were collected, and in-hospital mortality was calculated in both groups. The overall mortality of the study population was 25.3% (130 of 514 patients) with 96 (73.8%) being hypertensive and 34 (26.2%) being normotensive (p-value of 0.01, statistically non-significant association). The mortality rate among the hypertensive was higher as compared to non-hypertensive; however, hypertensive patients were more likely to be old and have underlying comorbidities including obesity, diabetes mellitus, coronary artery disease, congestive heart failure, stroke, chronic kidney disease (CKD), chronic obstructive pulmonary disease (COPD), and cancer. Therefore, multivariable logistic regression failed to show any significant association between hypertension and COVID-19 mortality. To our knowledge, few studies have shown an association between hypertension and COVID-19 mortality after adjusting confounding variables. Our study provides further evidence that hypertension is not an independent risk factor for in-hospital mortality when adjusted for other comorbidities in hospitalized COVID-19 patients.

Dual G9A/EZH2 Inhibition Stimulates Antitumor Immune Response in Ovarian High-Grade Serous Carcinoma.

Ovarian high-grade serous carcinoma (HGSC) prognosis correlates directly with presence of intratumoral lymphocytes. However, cancer immunotherapy has yet to achieve meaningful survival benefit in patients with HGSC. Epigenetic silencing of immunostimulatory genes is implicated in immune evasion in HGSC and re-expression of these genes could promote tumor immune clearance. We discovered that simultaneous inhibition of the histone methyltransferases G9A and EZH2 activates the CXCL10-CXCR3 axis and increases homing of intratumoral effector lymphocytes and natural killer cells while suppressing tumor-promoting FoxP3+ CD4 T cells. The dual G9A/EZH2 inhibitor HKMTI-1-005 induced chromatin changes that resulted in the transcriptional activation of immunostimulatory gene networks, including the re-expression of elements of the ERV-K endogenous retroviral family. Importantly, treatment with HKMTI-1-005 improved the survival of mice bearing Trp53-/- null ID8 ovarian tumors and resulted in tumor burden reduction. These results indicate that inhibiting G9A and EZH2 in ovarian cancer alters the immune microenvironment and reduces tumor growth and therefore positions dual inhibition of G9A/EZH2 as a strategy for clinical development.

The Genomic Landscape of Early-Stage Ovarian High-Grade Serous Carcinoma.

PURPOSE: Ovarian high-grade serous carcinoma (HGSC) is usually diagnosed at late stage. We investigated whether late-stage HGSC has unique genomic characteristics consistent with acquisition of evolutionary advantage compared with early-stage tumors. EXPERIMENTAL DESIGN: We performed targeted next-generation sequencing and shallow whole-genome sequencing (sWGS) on pretreatment samples from 43 patients with FIGO stage I-IIA HGSC to investigate somatic mutations and copy-number (CN) alterations (SCNA). We compared results to pretreatment samples from 52 patients with stage IIIC/IV HGSC from the BriTROC-1 study. RESULTS: Age of diagnosis did not differ between early-stage and late-stage patients (median 61.3 years vs. 62.3 years, respectively). TP53 mutations were near-universal in both cohorts (89% early-stage, 100% late-stage), and there were no significant differences in the rates of other somatic mutations, including BRCA1 and BRCA2. We also did not observe cohort-specific focal SCNA that could explain biological behavior. However, ploidy was higher in late-stage (median, 3.0) than early-stage (median, 1.9) samples. CN signature exposures were significantly different between cohorts, with greater relative signature 3 exposure in early-stage and greater signature 4 in late-stage. Unsupervised clustering based on CN signatures identified three clusters that were prognostic. CONCLUSIONS: Early-stage and late-stage HGSCs have highly similar patterns of mutation and focal SCNA. However, CN signature analysis showed that late-stage disease has distinct signature exposures consistent with whole-genome duplication. Further analyses will be required to ascertain whether these differences reflect genuine biological differences between early-stage and late-stage or simply time-related markers of evolutionary fitness. See related commentary by Yang et al., p. 2730.

Epithelial-to-Mesenchymal Transition Supports Ovarian Carcinosarcoma Tumorigenesis and Confers Sensitivity to Microtubule Targeting with Eribulin.

Ovarian carcinosarcoma (OCS) is an aggressive and rare tumor type with limited treatment options. OCS is hypothesized to develop via the combination theory, with a single progenitor resulting in carcinomatous and sarcomatous components, or alternatively via the conversion theory, with the sarcomatous component developing from the carcinomatous component through epithelial-to-mesenchymal transition (EMT). In this study, we analyzed DNA variants from isolated carcinoma and sarcoma components to show that OCS from 18 women is monoclonal. RNA sequencing indicated that the carcinoma components were more mesenchymal when compared with pure epithelial ovarian carcinomas, supporting the conversion theory and suggesting that EMT is important in the formation of these tumors. Preclinical OCS models were used to test the efficacy of microtubule-targeting drugs, including eribulin, which has previously been shown to reverse EMT characteristics in breast cancers and induce differentiation in sarcomas. Vinorelbine and eribulin more effectively inhibited OCS growth than standard-of-care platinum-based chemotherapy, and treatment with eribulin reduced mesenchymal characteristics and N-MYC expression in OCS patient-derived xenografts. Eribulin treatment resulted in an accumulation of intracellular cholesterol in OCS cells, which triggered a downregulation of the mevalonate pathway and prevented further cholesterol biosynthesis. Finally, eribulin increased expression of genes related to immune activation and increased the intratumoral accumulation of CD8+ T cells, supporting exploration of immunotherapy combinations in the clinic. Together, these data indicate that EMT plays a key role in OCS tumorigenesis and support the conversion theory for OCS histogenesis. Targeting EMT using eribulin could help improve OCS patient outcomes. SIGNIFICANCE: Genomic analyses and preclinical models of ovarian carcinosarcoma support the conversion theory for disease development and indicate that microtubule inhibitors could be used to suppress EMT and stimulate antitumor immunity.

Hilar lymphadenopathy, a novel finding in the setting of coronavirus disease (COVID-19): a case report.

BACKGROUND: As the outbreak of coronavirus disease 2019 (COVID-19) has progressed, computed tomography has emerged as an integral part of the diagnosis alongside reverse transcriptase-polymerase chain reaction assays. Frequently encountered imaging findings include peripheral airspace consolidations; bilateral ground-glass opacities; and, less commonly, cavitation. Hilar lymphadenopathy is a rarely reported finding in the setting of COVID-19. CASE PRESENTATION: A 73-year-old Caucasian woman presented to our hospital with fever and fatigue. She had a maximum body temperature of 102.3 °F with lymphopenia and thrombocytopenia. She was diagnosed with severe acute respiratory syndrome coronavirus 2 infection on the basis of a positive result from a reverse transcriptase-polymerase chain reaction of a nasopharyngeal swab sample. Contrast-enhanced chest computed tomography revealed multifocal, subpleural ground-glass opacities with nodular consolidations bilaterally. Computed tomography also demonstrated atypical bilateral hilar lymphadenopathy, a rarely reported imaging feature of COVID-19. Chest computed tomography 1 month before the presentation did not show focal consolidations or lymphadenopathy. This indicated that the findings were due to the patient's severe acute respiratory syndrome coronavirus 2 infection. She received 5 days of oral hydroxychloroquine and experienced resolution of her symptoms. CONCLUSION: Chest computed tomography has been used extensively to diagnose and characterize the distinguishing radiological findings associated with viral pneumonia. It has emerged as an integral part of the diagnosis of COVID-19 alongside reverse transcriptase-polymerase chain reaction assays. Clinicians must be aware of uncommon clinical and radiological findings in order to diagnose this entity. Hilar lymphadenopathy is commonly seen with fungal infections, mycobacterial infections, and sarcoidosis. An extensive literature review found that bilateral hilar lymphadenopathy has not been reported in the setting of COVID-19. More data are needed to establish the clinical impact of this novel finding.

E-cigarette or vaping product use associated lung injury, (EVALI) - A diagnosis of exclusion.

Inhalation of aerosolized products generated by different electronic devices is called vaping. E-cigarettes or Vaping product use Associated Lung Injury (EVALI) outbreak peaked in August-September 2019 and gradually declined. EVALI remains a diagnosis of exclusion which presents as an acute lung injury in the vaping population. Vitamin E acetate and its products are implicated as one of the cytotoxic agents causing airway centered pneumonitis. Lipid laden macrophages are found in samples of BAL fluid but their role in cytopathology of the disease remains unclear. We present a 57 years old man who came to the emergency department at Monmouth Medical Center, New Jersey in fall, 2019. Reportedly he has been vaping THC about 100g every day for past three days. At initial presentation, he had fever, shortness of breath and hypoxia requiring supplemental oxygen. He was empirically treated with levofloxacin 500 mg for five days without a significant improvement in his symptoms. Non-contrast chest CT scan showed bilateral ground-glass opacities, indicative of diffuse alveolar damage. He underwent flexible bronchoscopy to rule out infective pneumonia followed by auto-immune work-up that was non-conclusive. He was given 1 mg/kg methylprednisolone with a quick taper of oral steroids leading to the resolution of symptoms. At six months follow-up, imaging showed near resolution of ground-glass opacities.