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Context.— Associations between granulomatous lobular mastitis (GLM) and Corynebacterium kroppenstedtii have been reported since 2002, but large-scale studies to assess the actual prevalence of this bacterium in GLM have not been performed. Objective.— To assess the prevalence of C kroppenstedtii in GLM using real-time polymerase chain reaction and Sanger sequencing. Design.— We analyzed formalin-fixed, paraffin-embedded tissues from 67 cases of GLM by sequential DNA amplification and sequencing to assess the rate of C kroppenstedtii detection in GLM. A retrospective analysis including patient demographics, history of pregnancy and lactation, clinical signs and symptoms, radiographic findings, histologic pattern, Gram stain results, and microbial cultures was performed on 67 cases of GLM. In addition, 10 cases of nongranulomatous breast abscess were included as controls. Results.— C kroppenstedtii 16S rRNA SYBR real-time polymerase chain reaction was positive on formalin-fixed, paraffin-embedded tissues from 46 of 67 (68.7%) GLM cases, while all control cases were negative. Among the positive cases, the majority showed features of cystic neutrophilic granulomatous mastitis. Conclusions.— C kroppenstedtii was highly prevalent in GLM cases and was not found to be associated with nongranulomatous breast abscess in our study (P < .001).

Introduction: Patients with TNBC breast cancer have inferior treatment outcomes compared to other breast cancer subtypes and targeted therapies are lacking. S-equol is a novel oral Estrogen Receptor (ER) Beta agonist with preclinical data showing suppression of TNBC cellular proliferation, and recently presented data showed a decrease in Ki-67 in patients treated with S-equol. This abstract will present the molecular markers that correlate with Ki-67 change in patients with TNBC treated with neoadjuvant S-equol. Methods: We conducted a neoadjuvant window trial that enrolled 39 patients with confirmed TNBC on diagnostic core needle biopsy. Cohort A (20 patients) received a daily dose of 50 mg PO twice daily and Cohort B (19 patients) received a higher dose of 150 mg twice daily. Paired biopsies were evaluable for 36 patients. Both cohorts were treated for a duration of 10-21 days. Primary outcome was change from pre- to post-treatment Ki-67 evaluated by paired t-test and that data was previously published. Secondary endpoints include: Tumor infiltrating lymphocytes in intratumoral and peritumoral (stromal) locations using CD3 (pan T cell) and CD8 (cytotoxic T cell) immunohistochemistry, density of lymphocytes per high power field (40x) for both locations in pre-treatment and post-treatment specimens, Cyclin-D1 protein expression in pre-treatment and post-treatment biopsies as percentage of total tumor cells in pre-treatment and post-treatment specimens, and total estrogen receptor-beta protein expression using immunohistochemistry qualitatively and quantitatively using All-red score in pre-treatment and post-treatment specimens.Results: The primary outcome of Ki-67 decrease of at least 20% from baseline was observed in 28% of the patients. This is a placeholder abstract and an updated abstract with the correlative molecular markers as outlined above will be provided. Conclusion: S-equol is a novel well tolerated oral ER-Beta agonist with inhibition of proliferation in patients with TNBC as measured by a decrease in Ki-67. RNA-seq data, also previously presented, supports potential immune activation during this short period of drug exposure. Future studies aim to evaluate S-equol as an immune activating agent for combination with immunotherapies such as checkpoint inhibitors in TNBC. The pending molecular predictors of response will inform future therapeutic clinical trials for this novel therapy. Citation Format: Kate Lathrop, Virginia Kaklamani, Andrew Brenner, Rong Li, Alia Nazarullah, Sarah Hackman, Courtney Thomas, Jonathan Gelfond, Marisa Rodriguez, Richard Elledge. Molecular markers of response to s-equol, a novel oral estrogen receptor (ER) beta agonist for triple negative breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS5-31.

Nuclear NADPH oxidase-4 (Nox4) is a key component of metabolic reprogramming and is often overexpressed in renal cell carcinoma (RCC). However, its prognostic role in RCC remains unclear. Here we examined the significance of nuclear Nox4 on disease progression and development of drug resistance in advanced RCC. We analyzed human RCC tissue from multiple regions in the primary index tumor, cancer-associated normal adjacent parenchyma, intravascular tumor in locally advanced cancer patients. We found that the higher nuclear Nox4 expression was significantly associated with progression and death. These findings were consistent after controlling for other competing clinical variables. In contrast, patients with lower nuclear Nox4, even in higher stage RCC had better prognosis. We identified a subset of patients with high nuclear Nox4 who had rapid disease progression or died within 6 months of surgery. In addition, higher nuclear Nox4 level correlated with resistance to targeted therapy and immunotherapy. Western blotting performed on fresh human RCC tissue as well as cell-lines revealed increased nuclear Nox4 expression. Our data support an important prognostic role of Nox4 mediated regulation of RCC independent of other competing variables. Nox4 localizes to the nucleus in high-grade, high-stage RCC. Higher nuclear Nox4 has prognostic significance for disease progression, poor survival, and development of drug resistance in RCC.

EBV-related lymphoproliferations in post-transplant settings range from non-destructive hyperplasia to polymorphic post-transplant lymphoproliferative disorder (PTLD) to overt lymphoma. Here we present two unusual cases of pediatric non-mass-forming gastrointestinal (GI) PTLDs with mixed pathologic features of non-destructive and polymorphic categories. Both patients were EBV naive and presented within 1 year of transplant with non-specific gastrointestinal symptoms (diarrhea, abdominal pain, and food intolerance) with hypoalbuminemia, cytopenia, and EBV viremia. No mass lesions were found on imaging and endoscopy. Random GI biopsies showed a non-mass-forming, but polymorphic-appearing lymphoid infiltrate with EBV positivity, monotypic plasma cells, and clonal B cells. Cyclophosphamide, steroids, and rituximab treatment had good clinical response in all cases, including one case which had poor response initially with rituximab alone. Based on these cases, we conclude that GI PTLD in children can present with vague abdominal symptoms, cytopenia, and hypoalbuminemia, and can be non-mass-forming and non-destructive. A high level of suspicion with random GI biopsies and clinicopathologic and laboratory correlation are required. Since these patients have no mass lesions, evaluating symptomatic relief, EBV viral load, improvement in cytopenia(s), serum albumin levels, and/or resolution of other systemic symptoms may be needed to monitor response to therapy.

Purpose: We evaluated the role of everolimus in the prevention of ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) progression. Experimental Design: The effects of everolimus on breast cancer cell invasion, DCIS formation, and DCIS progression to IDC were investigated in a 3D cell culturing model, intraductal DCIS xenograft model, and spontaneous MMTV-Her2/neu mouse model. The effect of everolimus on matrix metalloproteinase 9 (MMP9) expression was determined with Western blotting and IHC in these models and in patients with DCIS before and after a window trial with rapamycin. Whether MMP9 mediates the inhibition of DCIS progression to IDC by everolimus was investigated with knockdown or overexpression of MMP9 in breast cancer cells. Results: Everolimus significantly inhibited the invasion of human breast cancer cells in vitro. Daily intragastric treatment with everolimus for 7 days significantly reduced the number of invasive lesions from intraductal DCIS foci and inhibited DCIS progression to IDC in the MMTV-Her2/neu mouse mammary tumor model. Mechanistically, everolimus treatment decreased the expression of MMP9 in the in vitro and in vivo models, and in breast tissues from patients with DCIS treated with rapamycin for 1 week. Moreover, overexpression of MMP9 stimulated the invasion, whereas knockdown of MMP9 inhibited the invasion of breast cancer cell–formed spheroids in vitro and DCIS in vivo. Knockdown of MMP9 also nullified the invasion inhibition by everolimus in vitro and in vivo. Conclusions: Targeting mTORC1 can inhibit DCIS progression to IDC via MMP9 and may be a potential strategy for DCIS or early-stage IDC therapy.

Microscopic granulosa cell proliferations are rare incidental findings in ovarian and extraovarian tissue, and can simulate granulosa cell tumors. We report a case of a 22-yr-old nulliparous woman with incidental microscopic granulosa cell proliferation in the wall of an endometriotic cyst. Excision of the cyst revealed extensive endometriosis and incidental microscopic nests and cords of granulosa cells measuring 1.5 mm and positive for inhibin A and calretinin. A rare Call-Exner body was noted. An extensive literature review of both ovarian and extraovarian granulosa cell proliferations were performed to determine their possible origin, variable morphologic features and differential diagnosis. Forty-seven cases were identified occurring in pregnant (26%) and nonpregnant (74%) settings. The nonpregnant cases reveal an association with endometriosis and endometrioid adenocarcinomas. Follow-up data is very limited, but no reports of subsequent granulosa cell tumors are reported. We hypothesize that possible anovulation may play a role in the development of these proliferations. Because of unknown pathogenesis and limited follow-up data being available, their clinical significance and risk of neoplasia remain unclear.

A wide spectrum of hereditary syndromes predispose patients to distinct pancreatic abnormalities, including cystic lesions, recurrent pancreatitis, ductal adenocarcinoma, nonductal neoplasms, and parenchymal iron deposition. While pancreatic exocrine insufficiency and recurrent pancreatitis are common manifestations in cystic fibrosis and hereditary pancreatitis, pancreatic cysts are seen in von Hippel-Lindau disease, cystic fibrosis, autosomal dominant polycystic kidney disease, and McCune-Albright syndrome. Ductal adenocarcinoma can be seen in many syndromes, including Peutz-Jeghers syndrome, familial atypical multiple mole melanoma syndrome, Lynch syndrome, hereditary breast and ovarian cancer syndrome, Li-Fraumeni syndrome, and familial pancreatic cancer syndrome. Neuroendocrine tumors are commonly seen in multiple endocrine neoplasia type 1 syndrome and von Hippel-Lindau disease. Pancreatoblastoma is an essential component of Beckwith-Wiedemann syndrome. Primary hemochromatosis is characterized by pancreatic iron deposition. Pancreatic pathologic conditions associated with genetic syndromes exhibit characteristic imaging findings. Imaging plays a pivotal role in early detection of these conditions and can positively affect the clinical outcomes of those at risk for pancreatic malignancies. Awareness of the characteristic imaging features, imaging-based screening protocols, and surveillance guidelines is crucial for radiologists to guide appropriate patient management. ©RSNA, 2021.

We report a case of a 53-year-old woman with a CHEK2 mutation who was found on histology to have bilateral incidental Paget’s disease of the breast following bilateral prophylactic mastectomy.

Hematolymphoid neoplasms rarely involve the cervix, with an overall incidence of less than 1% among all cervical malignancies. Clinical presentations include abnormal uterine bleeding, pelvic discomfort, dyspareunia, back pain and vaginal discharge. Cervical Papanicolaou Smear is an important screening tool for early detection of cervical epithelial lesions; however, a high index of suspicion is needed to recognize non-epithelial malignancies like lymphoma. We report the case of a 48-year-old woman who presented with abnormal vaginal bleeding. Pap smear showed large atypical discohesive cells with vesicular chromatin and prominent nucleoli. A cell block preparation with immunohistochemistry confirmed large B-cell lymphoma. This diagnosis is important due to management strategy differences of chemoradiation over surgery in hematologic malignancies. A review of literature of hematologic malignancies diagnosed on Pap smear is also reported.

Pancreatic neuroendocrine neoplasms (panNENs) are heterogeneous neoplasms with neuroendocrine differentiation that show characteristic clinical, histomorphologic, and prognostic features; genetic alterations; and biologic behavior. Up to 10% of panNENs develop in patients with syndromes that predispose them to cancer, such as multiple endocrine neoplasia type 1, von Hippel-Lindau disease, tuberous sclerosis complex, neurofibromatosis type 1, and glucagon cell adenomatosis. PanNENs are classified as either functioning tumors, which manifest early because of clinical symptoms related to increased hormone production, or nonfunctioning tumors, which often manifest late because of mass effect. PanNENs are histopathologically classified as well-differentiated pancreatic neuroendocrine tumors (panNETs) or poorly differentiated pancreatic neuroendocrine carcinomas (panNECs) according to the 2010 World Health Organization (WHO) classification system. Recent advances in cytogenetics and molecular biology have shown substantial heterogeneity in panNECs, and a new tumor subtype, well-differentiated, high-grade panNET, has been introduced. High-grade panNETs and panNECs are two distinct entities with different pathogenesis, clinical features, imaging findings, treatment options, and prognoses. The 2017 WHO classification system and the eighth edition of the American Joint Committee on Cancer staging system include substantial changes. Multidetector CT, MRI, and endoscopic US help in anatomic localization of the primary tumor, local-regional spread, and metastases. Somatostatin receptor scintigraphy and fluorine 18-fluorodeoxyglucose PET/CT are helpful for functional and metabolic assessment. Knowledge of recent updates in the pathogenesis, classification, and staging of panNENs and familiarity with their imaging findings allow optimal patient treatment. ©RSNA, 2020.

Context.— Acute invasive fungal rhinosinusitis (AIFRS) is an aggressive form of fungal sinusitis, which remains a significant cause of morbidity and mortality. Early diagnosis and intervention are keys to improving patient outcomes. Intraoperative consultation has shown promise in facilitating early surgical intervention, but the accuracy of frozen section has not been clarified in this setting. Objectives.— To assess the accuracy of frozen-section diagnosis in patients with clinically suspected AIFRS. Design.— All cases of clinically suspected AIFRS during a 10-year period (2009–2019) were retrospectively reviewed. The frozen-section results were compared with the final permanent sections as well as the tissue fungal culture results, following which the accuracy of frozen section was determined. Results.— Forty-eight patients with 133 frozen-section evaluations for AIFRS were included in the study. Thirty of 48 patients and 61 of 133 specimens were positive for AIFRS on final pathology. Of 30 positive patients, 27 (90%) had at least 1 specimen diagnosed as positive during intraoperative consultation; among the 61 positive specimens, 54 (88.5%) were diagnosed as positive during intraoperative consultation. Of 72 negative specimens, all were interpreted as negative on frozen section. Thus, frozen sections had a sensitivity of 88.5% (95% CI, 0.78–0.97), specificity of 100% (95% CI, 0.94–1), positive predictive value of 100% (95% CI, 0.92–1), and negative predictive value of 90.6% (95% CI, 0.82–0.97). Conclusions.— This study represents the largest series assessing the diagnostic accuracy of frozen section analysis in AIFRS. These findings are useful in frozen section–informed intraoperative decision making.

Cytometry by time-of-flight (CyTOF) simultaneously measures multiple cellular proteins at the single-cell level and is used to assess intertumor and intratumor heterogeneity. This approach may be used to investigate the variability of individual tumor responses to treatments. Herein, we stratified lung tumor subpopulations based on AXL signaling as a potential targeting strategy. Integrative transcriptome analyses were used to investigate how TP-0903, an AXL kinase inhibitor, influences redundant oncogenic pathways in metastatic lung cancer cells. CyTOF profiling revealed that AXL inhibition suppressed SMAD4/TGFβ signaling and induced JAK1–STAT3 signaling to compensate for the loss of AXL. Interestingly, high JAK1–STAT3 was associated with increased levels of AXL in treatment-naïve tumors. Tumors with high AXL, TGFβ, and JAK1 signaling concomitantly displayed CD133-mediated cancer stemness and hybrid epithelial-to-mesenchymal transition features in advanced-stage patients, suggesting greater potential for distant dissemination. Diffusion pseudotime analysis revealed cell-fate trajectories among four different categories that were linked to clinicopathologic features for each patient. Patient-derived organoids (PDO) obtained from tumors with high AXL and JAK1 were sensitive to TP-0903 and ruxolitinib (JAK inhibitor) treatments, supporting the CyTOF findings. This study shows that single-cell proteomic profiling of treatment-naïve lung tumors, coupled with ex vivo testing of PDOs, identifies continuous AXL, TGFβ, and JAK1–STAT3 signal activation in select tumors that may be targeted by combined AXL–JAK1 inhibition. Significance: Single-cell proteomic profiling of clinical samples may facilitate the optimal selection of novel drug targets, interpretation of early-phase clinical trial data, and development of predictive biomarkers valuable for patient stratification.

OBJECTIVE To determine the frequency of vitamin-D deficiency in hepatitis C patients and its relation with demographic and baseline laboratory data. METHODS The cross-sectional study was conducted at the University Institute of Medical Laboratory Technology, Faculty of Allied Health Sciences, The University of Lahore, Pakistan, from April 3 to July 24, 2017, and comprised diagnosed hepatitis C genotype 3 patients aged 18-60 years. Demographic data was collected on a predesigned proforma. Tests included complete blood counts, liver function test, hepatitis C viral load and 25-hydroxy Vitamin-D level. Data was analysed using SPSS 24. RESULTS Of the 115 patients, 54(47%) were male and 61(53%) were females. Mean vitamin-D level was 22.3±11.3. Total 25(21.7%) patients showed normal level of vitamin-D while the level was low in 90(78.3%) patients; 41(35.6%) showed vitamin-D insufficiency and 49(42.6%) vitamin-D deficiency. Significant effect of sun exposure was recorded on patient's vitamin-D level (p=0.00). Significantly low hepatitis C viral load was seen in patients with normal vitamin-D (p= 0. 02 6 ). CONCLUSIONS Patients with hepatitis C virus infection had high incidence of hypo-vitaminosis D.

The histologic distinction between papillary breast lesions remains challenging, especially with core biopsy (CB) specimens. A retrospective review of the clinical, imaging, and histologic findings was performed for patients with papillary breast lesions on CB from 2013 to 2017. The interpretation accuracy was expressed as upgrade rate relative to the excision diagnosis. Diagnostic reproducibility with and without immunohistochemistry was analyzed as interobserver variability among 3 board-certified pathologists. Among 57 papillary lesions with biopsies and excisions available for review, the upgrade rates were 0% for benign papilloma, 30% for papilloma with atypical ductal hyperplasia, and 25% for papilloma with ductal carcinoma in situ, resulting in an overall upgrade rate of 11.1%. There were no statistical differences between patients in an upgrade group and others, when comparing the patient age, clinical presentation, BI-RADS (Breast Imaging Reporting and Database System) category, location, and histologic grade. The overall interobserver variability of the 60 consecutive core biopsies of papillary breast lesions by morphology alone was in the “substantial” agreement range (κ = 0.79, 86% agreement), with an excellent κ score of 0.88 for papilloma (92% agreement). “Substantial” and “fair” κ values were seen for papilloma with atypical ductal hyperplasia/ductal carcinoma in situ (0.74, 84% agreement) and invasive carcinoma (0.40, 60% agreement). Use of immunohistochemical stains improved the κ values into “excellent” range (0.92, 94% agreement). Our study favors a conservative approach in the management of benign papillomas, at least in cases of good radiologic-pathologic concordance. Papillary breast lesions with atypia/malignancy show lower diagnostic reproducibility on CB, and utility of immunohistochemistry is recommended in challenging cases.

Aggressive natural killer cell leukemia (ANKL) is a rare neoplasm of mature natural killer cells, with an extremely poor overall survival, which is almost always EBV related, with majority of cases reported in East Asia. Here we report the case of an ANKL presenting in a young Hispanic male with secondary hemophagocytosis. Aggressive clinical course, high EBV DNA levels and leukemic presentation, often with associated hemophagocytosis, should raise suspicion of an NK/T-cell neoplasm like ANKL. Due to significant diagnostic overlap with extranodal NK/T-cell lymphoma, nasal type (ENKL), accurate diagnostic classification is crucial due to differing treatment and prognosis. L-asparaginase including chemotherapy followed by allogeneic stem cell transplantation appears to slightly prolong overall survival, but relapse is almost inevitable. Clinical monitoring of EBV DNA levels shows good correlation with disease activity.

Follicular lymphoma (FL) is the most common type of B cell non-Hodgkin lymphoma in Western counties. FL is usually seen in adults and is very uncommon in pediatric population. Pediatric follicular lymphoma (PFL) is a rare indolent lymphoma characteristically seen in pediatric population, usually involving cervical lymph nodes, Waldeyer ring, and testis. They pose significant diagnostic challenges due to morphologic overlap with much more common florid follicular hyperplasia and lack of typical t(14;18)IgH/BCL2 fusion and BCL-2 protein expression. We present the case of a 10-year-old male with bilateral conjunctival nodules, showing characteristic morphologic and immunophenotypic features of PFL with demonstrated clonal B cell immunoglobulin heavy chain gene rearrangement. Of note, the neoplastic cells expressed MUM1, MYC, and IgM, suggestive of a different disease pathogenesis from adult FL.

Casestudy: A 74-year-old woman of Scottish descent presented with obstructive jaundice and weight loss. Imaging revealed a head of pancreas mass with extrahepatic bile duct dilation. Fine needle aspiration cytology of the mass was non-diagnostic, therefore the patient underwent a pancreaticoduodenectomy. Gross examination revealed a circumferential, necrotic lesion involving the periampullary duodenum with invasion into the pancreas and peri-pancreatic soft tissue. Microscopically, the lesion was composed of diffuse sheets of monomorphic medium-sized cells with fine chromatin, inconspicuous nucleoli, and scant pale cytoplasm. The duodenal mucosa overlying the lesion was ulcerated. Epitheliotropism was noted in the duodenal villi, crypt epithelium and pancreatic duct epithelium. The tumor showed extensive areas of necrosis and conspicuous perineural invasion. The duodenal mucosa uninvolved by the tumor showed no evidence of an underlying enteropathy, such as Celiac disease. By immunohistochemistry, the neoplastic cells were positive for CD45, CD3, CD8, CD56, TIA-1, granzyme B, TCR-BF1, and TCR-gamma, and were negative pan B-cell markers, CD4, CD5, CD25, CD30, EBER, HHV-8, and TCL-1. Molecular studies for T cell clonality revealed clonal TCR-alpha-beta and gamma-delta gene rearrangements. Given the morphologic and immunophenotypic findings, the diagnosis of monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) was rendered. This case is unique with features not typical of MEITL, namely mass-like pancreaticoduodenal presentation resulting in a Whipple resection, extensive necrosis, and perineural invasion.

560 Background: Patients with TNBC breast cancer have inferior treatment outcomes compared to other breast cancer subtypes and targeted therapies are lacking. S-equol is a novel oral Estrogen Receptor (ER) Beta agonist with preclinical data showing suppression of TNBC cellular proliferation. We therefore conducted an early phase window of opportunity trial to evaluate the impact of S-equol on Ki-67 change in patients with TNBC. Methods: This neoadjuvant window trial enrolled 39 patients with confirmed TNBC on diagnostic core needle biopsy. Cohort A (20 patients) received a daily dose of 50 mg daily and Cohort B (19 patients) received a higher dose of 150 mg daily. Paired biopsies were evaluable for 36 patients. Both cohorts were treated for a duration of 10-21 days. Primary outcome was change from pre- to post-treatment Ki-67 evaluated by paired t-test. All tests were 2-sided with a significance level of 0.05. Statistics were conducted within an accountable data analysis process in R (ADAPR). Secondary outcomes included toxicity and correlative biomarkers. Results: The mean (SD) pre-treatment was 68% (21.99) and post-treatment 59% (20.62). The average decrease in Ki-67 was 8% (P = 0.00206, 95% CI -13.46 to -3.26). A Ki-67 decrease of at least 20% from baseline was observed in 28% of the patients. S-equol was well tolerated with the most common toxicities being nausea, constipation, diarrhea, and headache. All toxicities were grade one. Treatment compliance was greater than 95%. Planned correlative studies included RNA-seq. A total of 161 genes are differentially expressed with fold change > = 2 and p value < 0.05. The top genes of the differential expression list include BMP5, S100A7, FABP7, SCGB2A2, CH507-338C24.1, and DUSP1. Gene Set Enrichment Analysis (GSEA) indicates that top enriched gene modules are related to interferon function and immune response, most of which are downregulated in the post-treatment group. Conclusions: S-equol is a novel well tolerated oral ER-Beta agonist with inhibition of proliferation in patients with TNBC as measured by a decrease in Ki-67. RNA-seq data supports potential immune activation during this short period of drug exposure. Future studies aim to evaluate S-equol as an immune activating agent for combination with immunotherapies such as checkpoint inhibitors in TNBC. Clinical trial information: NCT02352025 .

Exclusive discohesive tumor cells within intra-alveolar spaces is a rare pattern of involvement of primary and metastatic lung tumors. In the absence of a tumoral mass, this pattern closely mimics desquamative interstitial pneumonia (DIP) clinically, radiologically, and histologically. However, a secondary DIP pattern may be seen adjacent to a tumor mass not infrequently. Here, we describe a case of a 64-year-old woman status post bilateral lung transplantation, who was radiologically thought to have an interstitial lung disease. The autopsy lung specimen revealed extensive involvement by intra-alveolar adenocarcinoma, with a cytomorphology mimicking alveolar macrophages as seen in DIP in the absence of a tumoral mass. The presence of subtle clustering with signet ring cell features and rare micropapillae were an important clue to the diagnosis. The tumor cells were positive for CK7, napsin-A, and TTF-1, and negative for CD68. This case represents an unusual variant of pulmonary adenocarcinoma with a pure intra-alveolar pattern of involvement, mimicking DIP. To the best of our knowledge, excluding biopsy specimens, only one similar case has been reported in the literature and none in the posttransplant setting.

Background and objective Granulomatous lung disease (GLD) is caused by a wide range of conditions. Often there is a need to correlate pathological findings with clinical, microbiological or radiological data to determine an aetiology. The aim of this study was to determine the different aetiologies of GLD over the past decade. Methods Among 2228 consecutive lung specimens from 1999 to 2011, 226 cases (10.1%) were positive for GLD. One hundred ninety patients were retrospectively reviewed and diagnoses were assigned based on availability of histological/clinical/microbiological correlation. Results A confident, probable and uncertain diagnosis was made in 68.4%, 13.2% and 18.4% patients. The aetiologies comprised infectious, non-infectious and uncertain in 54.7%, 26.8% and 18.4% patients. Mycobacterial infections constituted 27% of all patients, and included atypical, tuberculous and unclassified mycobacteria in order of frequency. Acid-fast bacilli (AFB) were visualized in tissue sections in 29% cases and cultured in 73% cases. Fungal infections comprised 27% of all cases, which included Coccidioides, Cryptococcus, Aspergillus and Histoplasma in order of frequency. Fungi were visualized in tissue sections with Gomori methenamine silver (GMS) stain in 83% patients and cultured in 52% cases. Sarcoidosis was the major non-infectious aetiology, constituting 21% of all patients. Necrosis in granulomas was associated with the presence of infection (P

Background: Non-small cell lung cancer (NSCLC) is a molecularly heterogeneous disease with a high propensity for drug resistance and metastasis. AXL, a member of the Tyro3-AXL-Mer family of receptor tyrosine kinases, is a central regulator of epithelial-to-mesenchymal transition (EMT) and enables tumor cells to invade and acquire drug resistance. AXL is overexpressed in lung tumors, correlates positively with tumor invasion, drug resistance, and negatively predicts overall survival. We mechanistically interrogate the effects of AXL inhibitor TP-0903 on EMT in lung adenocarcinoma cells using transcriptomic and proteomic profiling. Methods: Atomic force microscopy, Western blot analysis, RNA sequencing and mass cytometry (CyTOF) were all used to scrutinize the biomechanical properties, phenotypic, transcriptomic and proteomic profiles of A549 cells treated with 40nM TP0903 or shAXL knockdown. Results: TP-0903 attenuates total AXL/AXL phosphorylation and blunts transcriptional responses to TGFβ-Hippo signaling by disrupting the transcriptional complexes formed by SMAD2/3, SMAD4, YAP1 and TAZ. AXL knockdown or TP-0903 reverses EMT phenotype and reduces migration potential in A549 and H2009 adenocarcinoma cell lines. CyTOF data also identified resistant clones that overexpress TGFβ receptor II, TAZ protein and display hybrid EMT phenotypes. Conclusions: We are the first to report the interplay between AXL and TGFβ-Hippo signaling axis. TP-0903 study agent has excellent therapeutic promise in NSCLC and we speculate that TP-0903 drug can target epithelial to mesenchymal transitional states in lung cancer cells possibly through the inhibition of the AXL-TGFβ-Hippo signaling axis. Citation Format: Josephine Amalia Taverna, Chia-Nung Hung, Chun-Lin Lin, Pawel Osmulski, Meizhen Chen, Chiou-Miin Wang, Nicholas L. L. Lucio, Nameer Kirma, Chih-Wei Chou, Maria E. Gaczynska, Alia Nazarullah, Mark Wade, Lars Mouritsen, Tim Huang. AXL inhibitor TP-0903 attenuates AXL-TGFbeta Hippo signaling axis in lung adenocarcinoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2193.

639 Background: NOX4 protein are involved in cell differentiation, migration and apoptosis. We recently demonstrated that NOX4 in renal cell carcinoma (RCC) is an energetic sensor and couples energy metabolism to drug-resistance. In this study we demonstrate that enhanced nuclear localization of NOX4 is correlated with poor survival. Methods: We identified 350 RCC patients with (n = 85) and without (n = 265) venous tumor thrombus (VTT) who underwent radical nephrectomy with or without thrombectomy at our institution between 2013-2016. Fifty patients with RCC and VTT were matched 1:1 to patients with RCC and no VTT. Tissue Microarray (TMA) consisting of primary renal tumor, adjacent renal tumor and VTT were created. These matched TMA (n = 174) were stained with NOX4 antibodies; scanned using the Aperio scanning system and analyzed with the ImageScope software. The RCC nucleus was evaluated for roundness, elongation and size. NOX4 nuclear staining was categorized based on intensity as either strong positive, moderate, weak or no localization. Differential protein expression between the primary tumor, adjacent normal parenchyma and VTT was assessed using the Chi-squared test or t-test. Progression-free survival (PFS) and overall-survival (OS), stratified by NOX4 staining intensity, was estimated using the Kaplan-Meier method and compared with the log-rank test. Cox regression model was used to investigate effect of NOX4 staining on survival in multivariate analyses. Results: NOX4 nuclear colocalization was higher in patients who had progression and death from RCC. On univariate analysis, the intensity of NOX4 protein expression in the nucleus was significantly associated with PFS (HR 1.67, 95%CI (1.08-2.57; p = 0.02) and OS (HR 2.31, 95%CI (1.26-4.24; p = 0.007). On multivariate analyses the association between NOX4 protein expression and OS remains statistical significance (HR 2.09, 95%CI (1.05-4.18, p = 0.037). Conclusions: We provide evidence that in high grade/high stage cancer, NOX4 is colocalized within the nucleus of RCC. The prognostic role of NOX4 was determined at the protein level. We provide rationale for further investigation of NOX4, which may serve as a checkpoint in RCC.

Although inflammatory myofibroblastic tumors (IMTs) can be found in virtually every major organ, cardiac origin is rare. After recently providing care to a child who presented with a significant myocardial infarction, interest in this rare tumor was piqued. We describe a comprehensive review of cardiac IMT, including information on nomenclature, epidemiology, clinical features, pathogenesis, gross/histological features, immunohistochemical profile, diagnosis, treatment, and prognosis. Fifty-seven cases were identified in the literature. Interestingly, our case represents the seventh case of coronary artery involvement reported. Moreover, it was found that an initial presentation of sudden death most commonly involves the coronary arteries.