Metastatic Disease In Patients Research Articles

Role of positron emission tomography-contrast enhanced computed tomography in locally advanced gallbladder cancer.

This study aims to define the role of flurodeoxyglucose (18F -FDG) positron emission tomography-contrast enhanced computed tomography (PETCECT) scan in upstaging disease in patients with locally advanced gallbladder cancer (LAGBC). An analysis of a prospectively maintained database of gallbladder cancer (GBC) patients was performed. Patients found to have locally advanced (T3 and/or T4 or N+) but non-metastatic disease on initial imaging, either a contrast enhanced computed tomography (CECT) or a magnetic resonance imaging (MRI) scan, underwent an additional PETCECT for staging and the results impacting treatment decision were recorded. One hundred and three patients of LAGBC underwent CECT/MRI and PETCECT. 48/103 (46.6%) were found to be upstaged to stage IV after PETCECT. The most common metastatic site was non-regional retroperitoneal lymph nodes (12 patients, 11.7%) followed by satellite lesions in liver (11, 10.7%). Fourteen (13.6%) patients had equivocal findings on PET scan that required confirmation by tissue sampling out of which 10 (71.4%) were subsequently found to have metastatic disease. The only statistically significant factor predicting distant spread on PETCECT was the presence of loco-regional nodes on CT scan (odds ratio6.15, P=.006). PETCECT is a valuable tool to rule out metastatic disease in patients presenting with LAGBC.

Abstract P6-04-13: Preclinical and clinical analyses of estrogen receptor alpha mutant metastatic breast cancer

Abstract Background: Estrogen receptor alpha (ER) positive breast cancer (BC) that recurs as metastatic disease in patients on aromatase inhibitor therapy often harbors mutations in the last exon of the ESR1gene. Such mutations result in amino acid alterations in the ligand binding domain that confer a selective advantage because they render ER constitutively active under estrogen depleted conditions. Hypothesis: We hypothesized that the selective survival advantages gained by metastatic ER mutant (ERmut) tumor cells would become evident in preclinical models simulating the clinical context in which they arise (estrogen deprivation, anchorage independence or metastatic outgrowth) that could then be confirmed in ER+ patient derived xenografts (PDX) and biopsies of metastatic disease. Methods: MCF7 and T47D cells expressing flag-tagged ERmut Y537S or D538G or flag-tagged ER wild type (ERw/t) at the endogenous locus were generated using CRISPR/Cas9. These cells were studied in standard culture conditions as compared to anchorage independent soft agar or poly-HEMA coated plate assays and under long-term estrogen deprivation (LTED) conditions in vitro as well as in vivo in ovariectomized (ovx) mice in late stage metastasis models. ER+ patient derived xenografts (PDX) with naturally occurring ERmutY537S (HCI-013EI) and ERmutL536P (HCI-007) (Dr. Alana Welm) were also studied in vivo. Colony formation assays and tumor growth were evaluated in the context of treatments targeting ER (fulvestrant), androgen receptors (AR) (enzalutamide), steroid hormone synthesis (CYP17 lyase inhibitor seviteronel), or BRD4 Bromo- and Extra-terminal Domain (BET) inhibitor (BETi: JQ1). Drug synergy was determined in vitro using CalcuSyn software or in vivo by tumor caliper measurement and in vivo imaging of tumor luciferase activity. Biopsies of metastatic ER+ BC from clinical trial NCT02953860 were assayed for ESR1 exon 8 mutations using a modified Archer VariantPlex Solid Tumor Assay and immunohistochemistry performed for the four main steroid hormone receptors. Results: ERmutY537S or D538G containing MCF7 and T47D cells exhibited significantly increased anchorage independent survival, a condition in which AR is uniquely upregulated, while ER, progesterone receptors (PR), and glucocorticoid receptors (GR) are not. Furthermore, anti-androgens abrogated the ERmut survival advantage in soft agar. LTED ERmut lines expressed significantly more AR than their non-LTED predecessors or ERw/t counterparts as did ERmut PDX as compared to ERw/t PDX. MCF7 and T47D ERmutY537S and D538G demonstrated a significant increase in AR protein upon anchorage independent survival as compared to ERw/t, with ERmutD538G expressing particularly elevated AR. Biopsies of metastases from consenting patients with ER+ BC confirmed significantly higher AR protein in ERmut metastases as compared to ERw/t by IHC. Treatment of mice with ERmut PDX with combination fulvestrant and anti-androgen decreased tumor growth as compared mice given vehicle control or fulvestrant only. The BET inhibitor JQ1 synergized with anti-androgen to significantly decrease proliferation of ERmut cells. In ovx mice, only ERmut metastases were detectable, while ERw/t did not thrive at metastatic sites. ERmut cells differentially expressed AR-regulated, metastasis-promoting genes and proteins, including chitinase 3-like 1 (CHI3L1), when compared to those with ERw/t. Conclusions: AR is induced by stress encountered during disease progression and treatment, such as anchorage independence and estrogen deprivation. Targeting AR may improve the efficacy of agents such as fulvestrant that inhibit ERmut metastatic disease or delay recurrence, as may agents such as BETi that affect the activity of both ER and AR. Citation Format: Jennifer K Richer, Michelle M Williams, Nicole S Spoelstra, Spencer Arnesen, Jessica L Christenson, Kathleen O’Neill, Jordan M Reese, Zannel D Blanchard, Toru Hanamura, Britta M Jacobsen, Jason Gertz, Anthony Elias. Preclinical and clinical analyses of estrogen receptor alpha mutant metastatic breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-04-13.

Embolization of Chest Neoplasms: The Next Frontier in Interventional Oncology?

The management of chest tumors and their sequelae has been an uncommon indication for transarterial embolization (TAE). More recently, vascular embolization has been increasingly performed for this indication. The most common reported indication for embolization of neoplastic disease in the chest is the control of bleeding resulting either from iatrogenic causes or from tumor invasion into a bronchus or vessel. A natural extension of the application of TAE to neoplasm-related hemoptysis is its burgeoning indication as a possible primary treatment for benign chest tumors, primary lung neoplasms, and metastatic disease in patients that are refractory to systemic therapies and have limited or no surgical options. The goals for this indication are tumor regression and management of bulk-related symptoms. In addition to bland TAE for this indication, authors have reported very initial results applying transarterial chemoembolization (TACE) and transarterial radioembolization (TARE) to chest neoplasms with promising results that support feasibility and safety. This article is an up-to-date review of the management of chest tumors with embolization and its variants.

Cartilage oligomeric matrix protein in patients with osteoarthritis is independently associated with metastatic disease in prostate cancer.

Metastatic prostate cancer has a 5-year survival rate of 30%. Identifying predictors of metastasis outcome could potentially reduce patient mortality. The objective of this study was to determine whether osteoarthritis had an impact on outcomes of prostate cancer including death, local recurrence and/or metastasis and to determine whether cartilage oligomeric matrix protein was involved. We performed a retrospective case-control study of patients with prostate cancer with and without the diagnosis of osteoarthritis and completed immunohistochemistry (IHC) analysis of prostate (n=20) and lymph node (n=7) surgical specimens. We evaluated death, local recurrence and metastatic disease by various IHC biomarkers including prostate specific membrane antigen (PSMA), cartilage oligomeric matrix protein (COMP), CD31, and Ki-67.Our model identified osteoarthritis as an independent risk factor for metastatic disease (OR 5.24, 95% CI 1.49 - 18.41). Most notably, when joint arthroplasty was included in the model, osteoarthritis was no longer an independent risk factor for this outcome (p=0.071). IHC demonstrated that those with osteoarthritis, had greater expression of COMP in the prostate samples (mean 23.9% vs 5.84%, p<0.05) but not of Ki-67, CD31, or PSMA. This study identified and quantified increased metastatic disease in patients with osteoarthritis. Also, patients with osteoarthritis expressed increased COMP levels in the prostate and most likely in distant lymphatic nodes. Moreover, our findings suggest that joint arthroplasty may affect the ability of osteoarthritis to promote metastasis, which could impact treatment protocols and survival outcomes of the most common cause of cancer-related death (metastasis) in the United States.

Whole-Body [18F]FDG-PET/MRI vs. [18F]FDG-PET/CT in Malignant Melanoma.

To assess the diagnostic performance of simultaneous whole-body 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) positron emission tomography (PET)/magnetic resonance imaging (MRI) compared to [18F]FDG PET/x-ray computed tomography (CT) for detection of distant metastatic disease in patients with malignant melanoma. We included patients with malignant melanoma who underwent a single injection [18F]FDG dual-imaging protocol that included whole-body PET/CT and subsequent whole-body PET/MRI for staging or restaging purposes in a prospective setting. Images from both modalities were analyzed by two rater teams for the presence of metastatic lesions. PET/CT-PET/MRI overall agreement as well as region-based accuracies, sensitivities (Se), and specificities (Sp) were computed. Between July 2014 and December 2018, 22 patients were enrolled. Interrater agreement and overall accuracy (consensus reading) were 78.8% (95% CI 71-84.9) and 96.1% (95% CI 92.3-98) for PET/MRI and 78% (70.2-84.3) and 97.4% (95% CI 93.7-98.9) for PET/CT, respectively (P = 0.42). PET/MRI reached a region-based Se of 89.1% (95% CI 79.4-94.5) and a Sp of 100%, whereas PET/CT showed a region-based Se of 92.7% (95% CI 84-96.9) and a Sp of 100% for the detection of metastatic disease in malignant melanoma. Whole-body [18F]FDG-PET/MRI appears to be comparable to [18F]FDG-PET/CT for lesion detection in patients with malignant melanoma.

How many lymph nodes are enough? Assessing the adequacy of lymph node yield for staging in favorable histology wilms tumor

PurposeCurrent investigational priorities in the treatment of favorable histology Wilms tumor (FHWT) center on accurate staging and risk-stratification. The extent of lymph node (LN) sampling has not been clearly defined; its importance cannot be overstated as it guides adjuvant therapy. The identification of a minimum LN yield to minimize the risk of harboring occult metastatic disease could help development of surgical guidelines. This study focuses on using the beta-binomial distribution to estimate the risk of occult metastatic disease in patients with FHWT. Materials & methodsThe National Cancer Database was queried for patients with unilateral FHWT from 2004 to 2013. Data were used to characterize nodal positivity for patients who underwent surgery and had ≥1 positive LN and ≥2 LNs examined. The probability of missing a positive LN (i.e., false negative) for a given LN yield was calculated using an empirical estimation and the beta-binomial model. Patients were then stratified by tumor size. Results422 patients met study criteria. To limit the chance of missing a positive LN to ≤10%, the empirical estimation and beta-binomial model estimated that 6 and 10 LNs needed to be sampled, respectively. Tumor size did not influence the result. Internal validation showed little variation to maintain a false negative rate ≤ 10%. ConclusionsUsing mathematical modeling, it appears that the desired LN yield in FHWT to reduce the risk of false-negative LN sampling to ≤10% is between 6 and 10. The current analysis represents an objective attempt to determine the desired surgical approach to LN sampling to accurately stage patients with FHWT. Level of evidenceII

Evaluating the prognostic significance of significant weight loss in patients with stage III non-small cell lung cancer (NSCLC) undergoing definitive chemoradiation (CRT) after FDG-PET staging.

e20045 Background: In the pre-PET era, weight loss is a harbinger of occult metastatic disease in patients with stage III NSCLC. Identifying the relationship between weight loss and pattern of relapse (POR), may enable stratification of patients into prognostic groups associated with increased risk of relapse. We sought to identify if weight loss remains a negative independent prognostic factor after FDG-PET staging. Methods: A retrospective audit (using web-based and electronic databases) was conducted in all patients with stage III NSCLC treated with definitive CRT between 01/07/2013 and 30/06/2018 at the Royal Brisbane and Women’s Hospital and The Prince Charles Hospital, Queensland, Australia. A descriptive analysis was applied to describe the primary end-point of PFS and secondary end-points of OS and POR, in relation to the percentage of pre-treatment weight loss (0-10% vs &gt; 10-20% vs &gt; 20%). A subset analysis looked at other prognostic factors identified in NSCLC to account for potential confounders. Results: Of the 127 patients (mean age 65 years, mean weight 76kg, 57% male, 42% current smokers) who commenced treatment during the study period, 24% lost &gt; 10% and 3% lost &gt; 20% weight. Median TTP for the entire cohort was 9 months. Based on multivariable modelling, risk of PD or death was 45% higher with &gt; 10% loss of body weight (p = 0.004), and risk of death was 36% higher with &gt; 10% of body weight (p = 0.05). Of the 54% that died during follow-up, 31 had distant PD, 18 had locoregional PD, 6 had local PD, and 10 had no PD. Males were at increased risk of PD. Conclusions: A prognostic link continues to be identified between significant (&gt; 10%) weight loss and risk of progressive disease or death in stage III NSCLC treated with definitive CRT despite pre-treatment FDG-PET. These findings identify a sub-group of patients where weight loss could still be a surrogate for micro-metastases not detected on PET, or other adverse prognostic markers. Other treatment strategies or improved diagnostic strategies are warranted.

P22 - Does Fiducial Marker Placement Prior to SBRT Increase the Risk of Metastatic Disease in Patients with Unresectable Pancreatic Cancer?

P22 - Does Fiducial Marker Placement Prior to SBRT Increase the Risk of Metastatic Disease in Patients with Unresectable Pancreatic Cancer?

The Utility of Whole Body Imaging in the Evaluation of Solitary Brain Tumors

Solitary brain tumors can propose a diagnostic dilemma owing to the difficulty in differentiating between primary brain tumors and metastatic disease. The similar radiologic appearance on routine magnetic resonance imaging will necessitate the need for additional noninvasive testing. We sought to determine the clinical utility of preoperative whole body screening with computed tomography (CT) to detect metastatic disease in patients with solitary brain tumors. A prospectively maintained surgical database for a large quaternary care academic institution was retrospectively reviewed for all patients undergoing craniotomy for a new diagnosis of enhancing solitary brain lesion from January 2011 to January 2016. Patients were excluded if the imaging findings had demonstrated multiple brain tumors, they had a known diagnosis of malignancy, or they had undergone previous craniotomy. The demographic and radiographic information and clinical and histopathologic data were collected and tallied. A total of 218 patients with solitary brain tumors met the inclusion criteria and were included in the present study. Histopathologic analysis confirmed primary central nervous system tumors in 152 patients (74.4%) and metastatic disease in 66 (25.6%). Preoperative screening with whole body CT had a sensitivity of 0.92 and specificity of 0.95 for detecting systemic metastases in the patients. Preoperative whole body CT correctly identified systemic malignancy in 88% of the patients ultimately diagnosed with metastasis (positive predictive value, 88%). Of those with negative whole body imaging findings, 97% had a diagnosis of a primary central nervous system neoplasm (negative predictive value, 97%). Preoperative whole body CT had a positive predictive value of 88% and negative predictive value of 97% in the present study and was both sensitive (92%) and specific (95%) for the detection of extracranial tumors. The identification of extracranial tumors on whole body CT screening might alter management.

Superior detection of metastatic cystic lymphadenopathy in patients with papillary thyroid cancer by utilization of thyroglobulin washout

Fine-needle aspiration (FNA) cytology has been the standard of care in the workup of cervical lymph nodes (LNs) in patients with recurrent papillary thyroid cancer (PTC) and suspicious cervical LNs. Recently, FNA thyroglobulin (TG) washout measurement has been proposed as an adjunct in the management of these patients. We hypothesize that using FNA-TG washout for suspicious cervical LNs would increase the accuracy of diagnosing metastatic disease especially in cystic and highly vascular cervical LN in patients with recurrent PTC. This is a retrospective study of a prospectively collected database for patients with thyroid cancer who underwent preoperative FNA followed by selective neck dissection by one surgeon at an academic institution. FNA-cytology and FNA-TG washout were performed simultaneously. A total of 138 patients were included in our study, of which 92 (66.7%) had undergone surgical intervention. Results of both methods were then correlated with the final surgical pathology. FNA-cytology alone showed a sensitivity of 80.0%, specificity of 100.0% with a negative predictive value (NPV) of 60.0%. By contrast, FNA-TG washout had a sensitivity of 95.8%, specificity of 90.5% with a NPV of 86.4%. Combination of the FNA-cytology with FNA-TG washout of cystic/highly vascular LN increased the accuracy of diagnosis with a sensitivity of 98.2%, specificity of 100.00% with a NPV of 95.0%. All 14 malignant cervical LNs with false-negative FNA-cytology showed elevated FNA-TG washout, 10 (71.4%) of which were cystic in nature and 4 were highly vascular on ultrasonography. FNA-TG washout increases the diagnostic accuracy in detecting metastatic disease in patients with recurrent thyroid cancer. FNA-TG washout may be of special diagnostic importance in cystic or highly vascular LNs, which might have falsely negative cytology. 2B.

Incidence and risk factors for abdominal occult metastatic disease in patients with pancreatic adenocarcinoma.

The incidence of occult metastatic disease (OMD) in pancreaticductal adenocarcinoma (PDAC) and associated risk factors are largely unknown. We identified all patients with PDAC, who had an aborted oncologic operation due to OMD within a 10-year period. The cases were matched to a cohort of resected PDAC patients on a 1:3 ratio, based on age and sex, for comparison of preoperative clinical characteristics and potential risk factors for OMD. In the studied period, 117 patients with OMD were identified in 1423 pancreatectomies performed for PDAC (8%). Liver metastases were the most common finding (79%) followed by peritoneal implants (16%). When compared with non-OMD cases, patients with OMD presented more often with abdominal pain (P < 0.001), and higher preoperative carbohydrate antigen 19-9 (CA 19-9) values ( P = 0.007). Additionally, indeterminate liver lesions on preoperative computed tomography (CT) were identified in 40% of OMD versus 17% of non-OMD patients ( P < 0.001). Multivariable analysis distinguished four independent predictors for OMD: indeterminate lesions on preoperative CT, tumor size > 30 mm, abdominal pain, and preoperative CA 19-9 > 192 U/mL. Occurrence of OMD in PDAC accounts for 8% of cases. Preoperative CA 19-9 > 192 U/mL, primary tumor size > 30 mm, and identification of indeterminate lesions in preoperative CT may indicate the need for diagnostic laparoscopy.

Prognostic Significance of Sites of Metastatic Disease in Patients with Bladder Cancer

Prognostic Significance of Sites of Metastatic Disease in Patients with Bladder Cancer

P3.01-79 Intracerebral Efficacy of Immune Check-Point Inhibitors in NSCLC Patients with Brain Metastases

The brain is a common site of metastatic disease in patients with non-small cell lung cancer (NSCLC). Approximately 30–50% of patients will develop brain metastases during the course of treatment. Several immune check-point inhibitors (ICIs) have shown efficacy against non–small-cell lung cancers (NSCLCs) and approved in second line setting. However, regarding ICIs intracerebral efficacy and tolerability in NSCLC patients with active brain metastases (BMs) remains unknown. We reviewed the medical charts of 49 patients with advanced NSCLC treated with ICIs between January 2016 and March 2018. The intracranial activity of ICIs in patients with brain metastases was assessed by brain magnetic resonance imaging (MRI) using RECIST v. 1.1 criteria. The primary endpoint was intracerebral objective response rate (IORR). Secondary endpoints included intracerebral control rate, intracerebral and general progression-free survival (PFS), overall survival (OS) and tolerance. Ten NSCLC patients with BMs were identified. The median age of patients was 61 years (range 44–80 years) and the majority of patients were male (n = 9; 90%). All patients were pretreated with stereotaxic radiosurgery (n = 7) or whole brain radiation therapy (n = 3). All but one patients received prior systemic treatment for NSCLC. Three patients received two prior lines of systemic therapy. Two patients were treated with pembrolizumab. Median follow-up was 5.7 (95% CI: 2.7–8.4) months. IORR and extracerebral response rate were, respectively, 0% (95% CI: 0–25.9%) and 20% (95% CI: 2.5–55.6%). Intracerebral control rate was 60% (95% CI: 26.2–87.8%). Median intracerebral and general PFS lasted 1.8 (95% CI: 0.9–7.1) and 2.8 (95% CI: 1.8–4.6) months, respectively. Median OS was 8.9 (95% CI: 4.9–not reached) months. No neurological adverse events occurred. ICIs might have the efficacy and favorable safety profile in NSCLC patients with BMs.

Breast Cancer as a Cause of Intestinal Obstruction? A Case Report

Annually, approximately 230?000 women and 2300 men are diagnosed with breast cancer. It is the second most common malignancy occurring in women in the United States. The most common type of breast cancer is ductal carcinoma while invasive lobular carcinoma (ILC) being the second (1). The most common sites of breast cancer metastasis are located in the liver, lung, brain and bones. Out of 12001 cases of primary breast cancer, Matsuda et al, reported 73 cases of GI spread, of which only 24 cases presented as colorectal metastatic disease. (2) Within the GI tract, the stomach and the small bowel are the most common metastatic sites of lobular carcinoma, whereas large intestine infiltration is rare. We report the case of a 67 years old female with history of infiltrating lobular carcinoma of the breast with bone and recent discovered brain metastasis that presented to the emergency room with abdominal pain. She complained of a two-week history of epigastric abdominal pain worsened by oral intake. There was associated nausea and vomiting of food content. She had been constipated lately, and her last bowel movement was four days before admission. A CT abdomen showed a wall thickening in the cecum and nearby ascending colon. A colonoscopy showed an ulcerated partially obstructing cecal mass. Surgery was consulted for removal of the mass; a Lap right hemicolectomy and end ileostomy was done with the removal of a 5 cm mass. It was positive for CK7, GATA3 and ER; but negative for CDX2 and CK20, supporting the diagnosis of metastatic breast carcinoma. It was positive for cytoplasmic p120 staining, consistent with a lobular phenotype. After surgery the patient was discharged with scheduled follow-ups<./p> As previously mentioned, the GI involvement of a breast tumor is very rare. Less than 1% of GI metastatic disease was noted in 2500 cases of primary breast cancer over an 18-year follow-up period. (3) It is more common to discover a second primary GI cancer in patients with prior history of breast cancer (4). This case shows the importance of understanding the clinical progression of this growing subtype of breast cancer. A high index of suspicion for possible GI metastatic disease in patients with a history of ILC, whether newly diagnosed or in remission, is needed. This patient presented with constipation due to obstruction but diarrhea can be our only symptom that should prompt a rapid investigation as ILC typically mimics macroscopic changes seen in IBD.1663 Figure 1. Cecal wall thickening corresponding to a mass formation.

DIAGNOSTIC CAPABILITIES OF SPECT/CT IN THE BONE METASTATIC DISEASE DETECTION IN PATIENTS WITH BREAST CANCER AND PROSTATE CANCER

Purpose. To assess the additional contribution of SPECT/CT, used in conjunction with planar osteoscintigraphy, in bone metastatic disease detection and its effect on the tactics of managing patients with breast cancer and prostate cancer. Materials and methods. The study included 1412 patients with established oncological diagnosis (breast cancer — 844 patients, prostate cancer — 568 patients), to which «whole body» planar osteoscintigraphy, and SPECT/CT were performed. In all patients included in the study, the fact of bone metastatic disease was established by the results of additional imaging techniques and follow up. Results. Bone metastatic disease was detected in 324 (23%) patients and excluded in 1088 (77%). SPECT/CT had higher diagnostic indices than planar osteoscintigraphy. Sensitivity, specificity and accuracy of bone metastatic disease detection of planar osteoscintigraphy were 91%, 71%, 76%, of SPECT/CT, 97%, 93%, 94%, respectively. The additional use of SPECT/CT in the second stage after the planar osteoscintigraphy in 337 (24%) patients from the general group (n=1412) led to a change in the results of the diagnostic test. Conclusions. The additional use of SPECT / CT in the second stage after the planar osteoscintigraphy allows to change the results of the diagnostic test in the evaluation of bone metastatic disease in patients with breast cancer and PCa, which can significantly affect the management tactics of patients.

Abstract 5178: MUC13 is a novel molecular signature, for early detection and metastatic colorectal cancer

Abstract Objective: Colorectal cancer (CRC) is a leading cause of cancer mortality affecting over a million people every year. Biological markers for early detection and distant metastatic disease in patients with CRC are not well defined. We have identified transmembrane mucin MUC13, which is expressed in normal colon mucosa to be highly expressed in colorectal cancer, but the underlying pathways and the signaling mechanisms involved in CRC pathogenesis are not known. Our studies suggest MUC13 correlation with demographic and clinicopathologic characteristics. Materials and Methods: Retrospective institutional tumor registry was reviewed to identify patients with resected colon adenocarcinoma. Archived FFPE tissue blocks were reviewed by an experienced pathologist. Selected representative tissue blocks were serially sectioned at 4 µm. IHC staining was performed using an in-house MAb for MUC13. Slides were digitally scanned and analyzed qualitatively as well as quantitatively using a modified H-score based on the intensity of expression and percentage of stained cells. MUC13 was correlated with disease stage, aggressiveness and inflammatory markers, indicating poor prognosis in CRC patients. MUC13 splice variants were probed using novel designed probes. MUC13 SNPs were identified using unbiased approach by analyzing dpGAP database. Results: 196 tissues, of which 56.1% were female, 52% were white, and the median age at resection was 70. 38 (19.4%) were stage I, 64 (32.7%) stage II, 84 (42.9%) stage III, and 10 (5.1%) stage IV. 100% of colon adenocarcinoma tissues stained positively for MUC13, including definitive tumor epithelial staining, little-to-no background stromal staining, and mild staining of adjacent normal colon mucosa. Typical colon adenocarcinoma cells exhibited strong apical membranous staining with varying degrees of cytoplasmic staining. Advanced stage tumors were noted to more frequently exhibit basolateral and/or circumferential membranous staining compared to early stage tumors which more frequently displayed apical membrane staining alone. Five MUC13 transcript variants were identified by database analysis. Two of the protein coding MUC13 variants (long and short) showed differential expression in aggressive cell lines and patient tissues. Cyclic turnover between the short and long isoforms were observed during Anoikis resistance, cortisol, alcohol and BAP treatments. SNPs have been associated with increased risk of cancer incidence or fatality. Relevant MUC13 SNPs have been identified through systematic analysis of patient databases (dpGAP database). Verification and correlation of identified SNPs with patient disease stage and prognosis will also be presented. Conclusion: This is the first study to correlate MUC13 expression with disease outcome. Alternative transcripts and single nucleotide polymorphisms gave genetic insight of the role of MUC13 in CRC pathogenesis. Citation Format: Manish K. Tripathi, Chidi Zacheaus, Kyle Doxtater, Zachary Stiles, Fatemeh Keramatnia, Nadeem Zafar, Mahul Amin, Meena Jaggi, Subhash Chauhan. MUC13 is a novel molecular signature, for early detection and metastatic colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5178.

Abstract 5191: Targeting CX3CR1 Impairs the reseeding and colonization of circulating tumor cells and decelerates metastatic progression

Abstract This study aims to understand the mechanisms and dynamics by which cancer cells, departing from existing metastases as circulating cancer cells (CTCs), further seed and colonize skeleton and soft tissues, expanding metastatic spreading and precipitating the clinical progression to terminal disease. We have previously shown that the chemokine receptor CX3CR1 is implicated in the metastatic seeding of breast cancer cells and that FX-68, a novel small-molecule antagonist for this receptor, effectively contains both number of lesions and total tumor burden in animal models of metastatic disease. Here we established that FX-68 impairs the reseeding of skeleton and soft tissue and that the CTCs unable to reseed and forced to remain in the blood eventually succumb to apoptotic death. The metastatic potential of CTCs was confirmed by reinoculation experiments as well as by forcefully mobilizing cancer cells from metastases back in the blood and assessing the number of additional lesions generated, in the presence and absence of FX-68. Furthermore, we found that prolonging the permanence of CTCs in the blood by targeting CX3CR1 with FX-68 improved exposure of cancer cells to the chemotherapy drugs doxorubicin or docetaxel significantly decreased tumor progression and extended overall survival. Finally, we found evidence that cancer cells seeding the skeleton despite the inhibition of CX3CR1 failed to develop into tumors, suggesting a role of CX3CR1 expression in the metastasis-initiating properties of breast cancer cells. In summary, our results strongly support developing CX3CR1 antagonists and promoting their clinical use, as this approach will provide novel and effective tools to contain the progression of metastatic disease in patients. Citation Format: Chen Qian, Asurayya Worrede-Mahdi, Ramanpreet Kaur, Fei Shen, Joseph Salvino, Olimpia Meucci, Alessandro Fatatis. Targeting CX3CR1 Impairs the reseeding and colonization of circulating tumor cells and decelerates metastatic progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5191.

Abstract SY01-01: Endocrine resistance in metastatic breast cancer: Mechanisms and new therapeutic strategies

Abstract SY01-01: Endocrine resistance in metastatic breast cancer: Mechanisms and new therapeutic strategies

Abstract 1916: Targeting adhesion signaling network blocks tumor growth in gallbladder cancer

Abstract 96 Normal 0 false false false EN-US X-NONE X-NONE /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-parent:""; mso-padding-alt:0cm 5.4pt 0cm 5.4pt; mso-para-margin:0cm; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:Calibri; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin;} Gallbladder cancer (GBC) is a highly fatal malignancy with a 5-year survival rate of 17.6%. The prognosis of GBC is poor due to the aggressive tumor biology, late presentation, complicated anatomic position, and advanced stage at diagnosis. Characterized by a poor response to chemotherapy and radiotherapy, locally advanced and metastatic disease in patients with GBC is often treated with chemotherapy with palliative purpose. Therefore, development of new effective therapies is urgently needed for the treatment of GBC. The aim of the current study is to evaluate whether triptolide and its water soluble analog Minnelide is effective against GBC cells. We have previously shown that triptolide/Minnelide reduces tumor growth in various cancer models via regulating epithelial -mesenchymal transition (EMT), an important mechanism underlying metastasis. In our preliminary findings using two GBC cell lines, GB-d1 and NOZ, we demonstrate that triptolide inhibits the proliferation of GBC cells. Mice harboring subcutaneous gallbladder tumors, treated with Minnelide, exhibited a significant reduction in tumor weights and volume. In order to elucidate the mechanism underlying triptolide/Minnelide mediated inhibition of cellular proliferation in GBC cells and reduction in tumor growth, we identified Aurora Kinase A (AURKA) and FAK as two new targets for triptolide action in GBC cells. Triptolide regulates the activity of AURKA and FAK via an adhesion signaling protein NEDD9 which regulates the activation of several oncogenic proteins including FAK and SRC. By targeting both FAK and AURKA, triptolide disrupts the integrity of focal adhesion structures via deregulating adhesion signaling network. In addition, by targeting AURKA in GBC cells triptolide inhibits the cap-dependent translation machinery via eukaryotic translation initiation factor 4E (eIF4E). Our preliminary findings regarding potential use of Minnelide in GBC are promising. &amp;lt;!–EndFragment–&amp;gt; Citation Format: Mahendra K. Singh, Kaustav Majumder, Bhuwan Giri, Nivedita Arora, Shrey Modi, Vrishketan Sethi, Claudia P. Garcia, Juan C. Roa, Vikas Dudeja, Sulagna Banerjee, Ashok K. Saluja. Targeting adhesion signaling network blocks tumor growth in gallbladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1916.

Brachytherapy in Spinal Tumors: A Systematic Review

Conventional external beam radiation and stereotactic radiosurgery are common radiation techniques used to treat spinal tumors. Intraoperative brachytherapy (BT) may serve as an alternative when other options have been exhausted or as an adjunct in combination with other therapies. The objective of this study was to systematically review the literature on BT use in spinal tumor surgery. PubMed and Embase databases were systematically queried for literature reporting the use of BT in the surgical treatment of spinal tumors. PRISMA guidelines were followed. A meta-analysis was performed. Of the 203 initial articles queried, 15 studies were included. Of the 370 total patients described, 78% were treated for spine metastases. Indications for BT included tumors refractory to previous treatments and inability to tolerate chemotherapy, radiation, and/or open surgery. Seed placement was the most common method of delivery (58%) compared with plaques (42%). BT was placed during an open procedure in 52%, and of the remaining percutaneous procedures, 47% were combined with cement augmentation. Tumor recurrence rates varied from 13% to 49%. Seven studies reporting visual analog scale scores reported significant improvement in pain control. BT was used to treat metastatic disease in patients who failed previous therapies and could not tolerate open surgery or further therapy. This review summarizes the major findings in the available literature pertaining to patient background, indications, and outcomes. Spinal BT seems to be a viable option for spine tumor treatment and should be made available at treating centers.