Citations

The increasing use of gastrointestinal endoscopic procedures has led to the recognition by histopathologists of non‐conventional (or special‐type) dysplasias of the gastrointestinal tract. These lesions can be recognised in association with prevalent underlying gastrointestinal conditions, such as Barrett oesophagus, chronic atrophic gastritis, and inflammatory bowel disease. The diagnosis of these special types can be challenging, and their biological behaviours are not fully characterised. The aim of this review is to provide a global view of non‐conventional dysplastic lesions observed in the various segments of the tubular gastrointestinal tract and describe their salient features. Furthermore, as the clinical implications of these various subtypes have not been broadly tested in practice and are not represented in most management guidelines, we offer guidance on the best management practices for these lesions.

Objective: This article reviews the anatomy, histology, and disease processes of pulmonary fissures, with emphasis on clinical implications of accessory and incomplete fissures. Conclusion: Accessory and incomplete pulmonary fissures are often overlooked during routine imaging but can have profound clinical importance. Knowledge of fissure anatomy could improve diagnostic accuracy and inform prognosis for oncologists, interventional pulmonologists, and thoracic surgeons.

Candida auris is an emerging fungal pathogen with cases reported in countries around the world and in 19 states within the United States as of August 2020. The CDC has recommended that hospitals perform active surveillance upon admission for patients with the appropriate risk factors. Currently, active surveillance requires that local hospitals send surveillance swabs to a public health laboratory for analysis. In this work, a real-time PCR assay was developed for the specific detection of C. auris from surveillance swabs, blood, and urine to enable rapid detection of this pathogen. The assay uses commercially available primers and reporter probes and it was verified on the LightCycler 480 PCR platform. Contrived specimens and prospectively collected composite groin/axilla surveillance swabs were used to validate the assay. The performance of the PCR assay on surveillance swabs was also compared to a second PCR assay targeting C. auris that was performed at the Minnesota Department of Health–Public Health Laboratory (MDH-PHL). Our PCR assay is able to detect and differentiate C. auris from closely related Candida species such as C. duobushaemulonii, C. haemulonii, and C. pseudohaemulonii on the basis of melting curve temperature differences.

Background During the severe acute respiratory syndrome Coronavirus 2 pandemic, there has been an increase in hyperinflammatory presentation in previously healthy children with a variety of cardiac manifestations. Our objective is to describe the cardiac manifestations found in an international cohort of 55 pediatric cases with multi‐system inflammatory syndrome during the severe acute respiratory syndrome Coronavirus 2 pandemic. Methods and Results We reviewed data on previously healthy pediatric patients (≤18 years) with structurally normal hearts who presented at hospitals in the United States, United Kingdom, Spain, and Pakistan with multi‐system inflammatory syndrome in children and had consultation with a pediatric cardiologist. Data collected included demographics, clinical presentation, laboratory values, electrocardiographic abnormalities, echocardiographic findings, and initial therapies. A total of 55 patients presented with multi‐system inflammatory syndrome in children. Thirty‐five patients (64%) had evidence of decreased left ventricular function, 17 (31%) had valvulitis, 12 (22%) with pericardial effusion, and 11 (20%) with coronary abnormalities. Twenty‐seven (49%) required intensive care unit admission and 24 (44%) had evidence of shock. Eleven patients (20%) fulfilled complete Kawasaki disease criteria and had lower NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide), D‐dimer, and ferritin levels compared with those who did not fulfill criteria. Electrophysiologic abnormalities occurred in 6 patients and included complete atrioventricular block, transient atrioventricular block, and ventricular tachycardia. Conclusions To our knowledge, we describe the first international cohort of pediatric patients with multi‐system inflammatory syndrome in children during the severe acute respiratory syndrome Coronavirus 2 pandemic with a range of cardiac manifestations. This article brings awareness and alertness to the global medical community to recognize these children during the pandemic and understand the need for early cardiology evaluation and follow‐up.

AbstractCOVID-19 is also manifested with hypercoagulability, pulmonary intravascular coagulation, microangiopathy, and venous thromboembolism (VTE) or arterial thrombosis. Predisposing risk factors to severe COVID-19 are male sex, underlying cardiovascular disease, or cardiovascular risk factors including noncontrolled diabetes mellitus or arterial hypertension, obesity, and advanced age. The VAS-European Independent Foundation in Angiology/Vascular Medicine draws attention to patients with vascular disease (VD) and presents an integral strategy for the management of patients with VD or cardiovascular risk factors (VD-CVR) and COVID-19. VAS recommends (1) a COVID-19-oriented primary health care network for patients with VD-CVR for identification of patients with VD-CVR in the community and patients' education for disease symptoms, use of eHealth technology, adherence to the antithrombotic and vascular regulating treatments, and (2) close medical follow-up for efficacious control of VD progression and prompt application of physical and social distancing measures in case of new epidemic waves. For patients with VD-CVR who receive home treatment for COVID-19, VAS recommends assessment for (1) disease worsening risk and prioritized hospitalization of those at high risk and (2) VTE risk assessment and thromboprophylaxis with rivaroxaban, betrixaban, or low-molecular-weight heparin (LMWH) for those at high risk. For hospitalized patients with VD-CVR and COVID-19, VAS recommends (1) routine thromboprophylaxis with weight-adjusted intermediate doses of LMWH (unless contraindication); (2) LMWH as the drug of choice over unfractionated heparin or direct oral anticoagulants for the treatment of VTE or hypercoagulability; (3) careful evaluation of the risk for disease worsening and prompt application of targeted antiviral or convalescence treatments; (4) monitoring of D-dimer for optimization of the antithrombotic treatment; and (5) evaluation of the risk of VTE before hospital discharge using the IMPROVE-D-dimer score and prolonged post-discharge thromboprophylaxis with rivaroxaban, betrixaban, or LMWH.

Abstract Tumor associated fibroblasts (TAFs) are important regulators of tumor growth and resistance to therapies. We have recently shown that lung TAFs in vitro respond to the antifibrotic drug nintedanib in adenocarcinoma (ADC) but not squamous cell carcinoma (SCC). We also showed that the tumor-promoting effects of TAFs are driven by different mechanisms in ADC and SCC, which remain to be elucidated. Tissue inhibitor of metalloproteinases 1 (TIMP-1) has been associated with poor prognosis in lung cancer, its expression is downregulated by nintedanib, and our preliminary results reveal that its putative receptor, CD63, is overexpressed in ADC patients compared to SCC, supporting a selective crosstalk between TAFs and cancer cells in ADC through TIMP-1 and CD63. The aim of this study was to test this hypothesis using in vitro preclinical models. Primary fibroblasts were obtained with the patient informed consent, and using protocols approved by the Ethics Committee of the Hospital Clinic. ADC-TAFs and SCC-TAFs were stimulated with TGF-β1 in the presence or absence of nintedanib, and the TIMP-1 content in their conditioned medium was determined by ELISA. TIMP-1 was knocked-down in ADC-TAFs by siRNA, and the corresponding conditioned medium was used to stimulate growth and invasion of the high-CD63 ADC cell line, H1437. Likewise, CD63 expression in H1437 cells was reduced by siRNA. Our in vitro results showed that TIMP-1 secretion induced by TGF-β1 is significantly larger in ADC-TAFs compared to SCC-TAFs. Likewise, nintedanib elicited a higher downregulation of secreted TIMP-1 in ADC-TAFs compared to SCC-TAFs. Of note, TIMP-1 from ADC-TAFs was necessary to induce growth and invasion of H1437 cells. Likewise, knocking-down CD63 in H1437 ADC cells was sufficient to reduce the growth and invasion elicited by the conditioned medium of TGF-β1 activated ADC-TAFs. Collectively, our results unveil a novel stroma-carcinoma crosstalk driven by TIMP-1 and CD63 selectively in lung ADC, and support that such heterotypic crosstalk may underlie the aberrant tumor-promoting effects of ADC-TAFs that are selectively downregulated by nintedanib. Citation Format: Paula Duch, Marta Gabasa, Rafael Ikemori, Marselina Arshakyan, Frank Hillberg, Noemí Reguart, Derek Radisky, Jordi Alcaraz. TIMP-1 in tumor-associated fibroblasts drives tumor progression in lung adenocarcinoma through CD63 interaction [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5091.

Abstract Background: The soluble form of the low affinity Interleukin 2 receptor alpha subunit (sCD25) is often elevated and correlates with inferior outcome in cancers, including follicular B lymphoma (FL). We recently reported a novel RNA aptamer-based assay designated as the LIRECAP assay (for Ligand-Receptor Complex-binding Aptamers) that allows for specific measurement of the fraction of CD25 occupied by IL2 in a biospecimen. The LIRECAP assay demonstrated that the fraction of sCD25 that circulates as an IL2-sCD25 complex varies considerably in B cell lymphoma patients (from 10% to 96% occupancy of sCD25 by IL2) and that this fractional occupancy was significantly higher in FL compared to diffuse large B cell lymphoma (Cancer Immunol Res. 2019. 7: 1511-1522). The prognostic significance of IL2-occupied and unoccupied sCD25 fractions is not known and the current studies were designed to study their effect on FL outcome. Methods: Determining total, unoccupied and IL2-occupied sCD25 levels: Using the LIRECAP assay, we evaluated the fractional IL2 occupancy of sCD25 in pretherapy serum samples from FL patients who were subsequently treated with standard chemoimmunotherapy. In addition, total sCD25 was determined by a commercially available Luminex assay kit. Levels of total sCD25, unoccupied sCD25, IL2-occupied sCD25 and ratios of unoccupied to IL2-occupied sCD25 were then calculated for each sample. Patients were followed for 24 months following therapy to determine whether they achieved or failed to achieve event-free survival (EFS 24) (N=10 per group). Results: Unoccupied sCD25 levels correlates with poor prognosis: Total sCD25 and IL2-occupied sCD25 levels did not correlate with EFS24 (p=0.085 and 0.404, respectively). However, levels of unoccupied sCD25 and the ratio of unoccupied to IL2-occupied sCD25 were significantly higher in patients who failed to achieve EFS24 (p=0.048 both). Conclusions and significance: Unoccupied sCD25, but not IL2-occupied sCD25, in FL patient serum correlates with poor outcome. This could, in part, be due to the ability of IL2-occupied sCD25, but not unoccupied sCD25, to induce Tregs, as we have reported previously. A higher Treg infiltration has also been shown to correlate with a better FL outcome. Taken together, these data suggest that unoccupied sCD25 can serve as an independent prognostic marker in FL. Further analysis in a larger cohort of patients, and assessment of the biological effects of unoccupied and IL2-occupied sCD25 is ongoing. Citation Format: Suresh Veeramani, Sue E. Blackwell, Paula Banuelos, Zhi-Zhang Yang, Stephen M. Ansell, George J. Weiner. Unoccupied and IL2-occupied soluble CD25 have distinct prognostic effects in follicular lymphoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4333.

Abstract Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults with a median survival of 14 months despite multimodal treatment. Patients with GBM tumors exhibit a post-resection recurrence rate of almost 100%. The tumor recurrence and treatment resistance properties of GBM reside in a stem-like cell population called Brain Tumor Initiating Cells (BTIC). Among primary GBMs, periventricular tumors exhibit worse survival than tumors distal to the lateral ventricles (LV), the cause for this worse outcome is not known. A potential explanation is the proximity of these tumors to the cerebrospinal fluid (CSF) and the neurogenic niche in the sub-ventricular zone (SVZ). Chemotactic signals present in the cerebrospinal fluid (CSF) regulate neural progenitor cells migratory response and differentiation profile. Our preliminary data show that cancer-derived CSF induces an increase in the migration and proliferation of GBM cells when compared to non-cancer CSF. We evaluated the transcriptome of human GBM cells in response to cancer and non-cancer CSF and identified alpha-1-antichymotrypsin (SERPINA3) as one of the genes that show higher over expression upon cancer CSF-stimulation. SERPINA3 is a circulating anti-protease that is produced and released in different tissues such as liver, prostate, lungs, endometrium and brain that is over-expressed in multiple cancers. We hypothesize that the overexpression of SERPINA3 in response to CSF is a contributing factor to the increase malignancy of periventricular GBM tumors. We tested this hypothesis in silico, in vitro and in vivo. Using TCGA and Rembrandt databases we observed a higher expression of SERPINA3 in brain tumor tissue compared to controls with no differences among GBM subtypes. In GBM patients, expression of SERPINA3 negatively affects survival expectancy. In vitro, Using intraoperative samples, we confirmed that SERPINA3 is overexpressed in brain cancer tissue by western-blot and qRT-PCR. Interestingly, we observed a higher nuclear localization of SERPINA3 in cancer tissue and cells. To determine if SERPINA3 has an effect on the malignancy of GBM cells, we silenced its expression using shRNA. SERPINA3 silencing induced a decrease in cell proliferation (p<0.05), as well as migration (p<0.05), and invasion (p<0.05). Remarkably CD133 expression and stem cell markers were decreased when SERPINA3 is silenced. In contrast, the addition of recombinant SERPINA3 induced an increase in cell migration (p<0.05) of GBM cells. Moreover, cancer CSF is no longer able to induce an increase in GBM cell migration in SERPINA3-KD cells (p<0.05). In vivo, mice orthotopically-injected with SERPINA3-KD cells showed a prolonged overall survival (p<0.05). In summary, our results support the hypothesis that SERPINA3 plays a key role in GBM malignancy in response to CSF and its inhibition results in a better outcome using GBM preclinical models. Targeting the CSF-GBM interaction is a potential therapeutic approach that remains to be explored. Citation Format: Montserrat A. Lara Velazquez, Natanael Zarco, Anna Carrano, Jordan Phillips, Paula Schiapparelli, Emily S. Norton, Stephanie Jeanneret, Teresita Corona, Jose Segovia, Kaisorn Chaichana, Yan Asmann, Alfredo Quinones Hinojosa, Hugo Guerrero-Cazares. Cerebrospinal fluid-responsive factor SERPINA3 induces an increase in the malignancy of glioblastoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3780.

Abstract PARP inhibitor (PARPi) resistance in high-grade serous ovarian carcinoma (HGSOC) can be acquired as a result of restored homologous recombination (HR) due to secondary or reversion mutations in HR genes, such as BRCA1, BRCA2, and RAD51C, or due to loss of BRCA1 promoter methylation (meBRCA1). We have demonstrated that homozygous meBRCA1 can be lost or reverted to heterozygous methylation following treatment with platinum-based chemotherapy, resulting in HR-competent PARPi-resistant tumors. RAD51C promoter methylation (meRAD51C) is detected in approximately 2% of HGSOC cases and, as with meBRCA1, is associated with gene silencing and HR deficiency. We are exploring PARPi response in meRAD51C preclinical models to determine clinical relevance. Two patient-derived xenograft (PDX) models of HGSOC with RAD51C gene silencing caused by meRAD51C have distinct meRAD51C profiles (measured by methylation-specific high-resolution melt analysis and targeted bisulfite next-generation sequencing), and different responses to PARPi treatment pressure. PDX PH039 loses methylation and regains RAD51C expression after only 2 cycles of PARPi retreatment (niraparib), resulting in PARPi-refractory tumors by cycle 3-4. Illumina EPIC methylation array analysis of PH039 revealed increasing global methylation losses following each round of PARPi treatment. Lack of meRAD51C stability and rapid development of PARPi resistance in PH039 may be due to the high degree of meRAD51C heterogeneity within the tumor favoring selection of pre-existing HR-competent clones under PARPi pressure. In contrast, PDX 183 has a relatively homogeneous and stable meRAD51C profile. We have multiple examples of using unique PDX models to demonstrate various important features of PARPi resistance, including loss of promoter methylation for BRCA1 vs. RAD51C. Thus, meRAD51C confers response to PARPi in HGSOC, but PARPi treatment pressure can cause loss of methylation and drug resistance in some tumors. The contrasting PARPi responses of these PDX provide a platform for the study of meRAD51C stability in vivo and may present therapeutic opportunities to improve meRAD51C durability and PARPi responses in patients. Citation Format: Kasenija Nesic, Rachel M Hurley, Cordelia McGehee, Olga Kondrashova, Maria I. Harrell, Giada V. Zapparoli, Ashan Musafer, Ming E. Wong, John Weroha, Xiaonan Hou, Hu Li, Vivian Negron, Kevin Peterson, Paula Schneider, Elizabeth M. Swisher, Melissa Southey, Alexander Dobrovic, Matthew Wakefield, Scott H. Kaufmann, Clare L. Scott. DNA repair gene promoter methylation patterns adapt and influence PARP inhibitor response [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr IA02.