Large Tumor Burden Research Articles

Unusual presentation of acute kidney injury with Tumour Lysis Syndrome

Tumour lysis syndrome (TLS) can cause acute kidney injury (AKI) by the breakdown of intracellular contents during treatment for malignancies with large tumour burden. We report a case with an unusual presentation of AKI needing renal replacement therapy. Investigation of the cause for AKI led to the diagnosis of an underlying malignancy (lymphoma). Treatment of a Bell’s palsy with steroids before presenting to our service has caused the AKI giving us the overarching diagnosis of TLS in this patient with lymphoma.

Diffusion Magnetic Resonance Imaging Phenotypes Predict Overall Survival Benefit From Bevacizumab or Surgery in Recurrent Glioblastoma With Large Tumor Burden.

Diffusion magnetic resonance (MR) characteristics are a predictive imaging biomarker for survival benefit in recurrent glioblastoma treated with anti-vascular endothelial growth factor (VEGF) therapy; however, its use in large volume recurrence has not been evaluated. To determine if diffusion MR characteristics can predict survival outcomes in patients with large volume recurrent glioblastoma treated with bevacizumab or repeat resection. A total of 32 patients with large volume (>20 cc or > 3.4 cm diameter) recurrent glioblastoma treated with bevacizumab and 35 patients treated with repeat surgery were included. Pretreatment tumor volume and apparent diffusion coefficient (ADC) histogram analysis were used to phenotype patients as having high (>1.24 μm2/ms) or low (<1.24 μm2/ms) ADCL, the mean value of the lower peak in a double Gaussian model of the ADC histogram within the contrast enhancing tumor. In bevacizumab and surgical cohorts, volume was correlated with overall survival (Bevacizumab: P=.009, HR=1.02; Surgical: P=.006, HR=0.96). ADCL was an independent predictor of survival in the bevacizumab cohort (P=.049, HR=0.44), but not the surgical cohort (P=.273, HR=0.67). There was a survival advantage of surgery over bevacizumab in patients with low ADCL (P=.036, HR=0.43) but not in patients with high ADCL (P=.284, HR=0.69). Pretreatment diffusion MR imaging is an independent predictive biomarker for overall survival in recurrent glioblastoma with a large tumor burden. Large tumors with low ADCL have a survival benefit when treated with surgical resection, whereas large tumors with high ADCL may be best managed with bevacizumab.

171P Transarterial chemoembolization (TACE) plus lenvatinib versus TACE plus sorafenib for hepatocellular carcinoma (HCC) with portal vein tumour thrombus (PVTT): A prospective randomized study

HCC with PVTT portends a worse prognosis. This study compared the efficacy and safety of cTACE plus lenvatinib (cTACE+LEN) to the most commonly utilized regimen, cTACE plus sorafenib (cTACE+SOR), in patients with HCC and PVTT. An open-label, single-center, prospective, randomized trial. Patients with previously untreated HCC complicated by type I-IV PVTT were randomized 1:1 to receive cTACE+LEN (LEN orally, 12 or 8 mg/d for bodyweight ≥60 or <60 kg) or cTACE+SOR (SOR orally, 400 mg BID). The primary endpoint was time to progression (TTP; time from randomization to disease progression), secondary endpoints included objective response rate (ORR), overall survival (OS) and toxicity. Tumor response was assessed using mRECIST. Prognostic factors were evaluated with a Cox regression analysis. SPSS v17.0 was used for all analyses. Between Dec 30, 2018 and May 31, 2020, 64 patients were randomized (cTACE+LEN, n=32; cTACE+SOR, n=32). Patients had a median age of 56 years, a male/female ratio of 13/3, the majority had type I/II PVTT (71.9%; n=46), 34.4% (n=22) had extrahepatic metastasis, and median tumor diameter was 9.0 cm (3.8−21.8). After a median follow-up of 12.5 months, patients in the cTACE+LEN group had a higher median TTP (4.7 vs 3.1 months, HR: 0.55 [95% CI: 0.32–0.97], P=0.037) and numerically higher ORR (50.0 vs 25.0%, P=0.07) and median OS (15.6 [95% CI: 7.7−23.5] vs 10.8 months [95% CI: 8.9−12.7], P=0.15) versus the cTACE+SOR group. A similar incidence of serious adverse events (n=4 vs 2, including gastrointestinal bleeding and hepatic failure), drug withdrawal and dose reduction occurred in the cTACE+LEN and cTACE+SOR groups, and no treatment-related deaths occurred during the study period. Objective response was identified as an independent predictor of favorable TTP (HR: 0.41 [95% CI: 0.22–0.75], P=0.004). cTACE+LEN was safe, well-tolerated, and had favorable efficacy versus cTACE+SOR for the treatment of advanced HCC with PVTT and large tumor burden. Differences in ORR and OS did not reach statistical significance, which may be due to the limited sample size and requires further study.

Outcome of Hepatocellular Carcinoma Detected During Surveillance: Comparing USA and Japan

Differences in outcomes of hepatocellular carcinoma (HCC) between countries have been largely attributed to variation in the conduct of surveillance and subsequent HCC treatment eligibility. However, differences in outcomes among those detected under surveillance have not been well described. We compared characteristics and prognosis between patients with surveillance-detected HCC from the United States (US) and Japan. Patients in whom initial HCC was detected under surveillance between January 2006 and December 2015 from two centers in the US and two from Japan were included. Survival was compared between patients from the US and Japan using multivariable Cox regression analysis and propensity-score matched analysis. We performed subgroup analyses by liver disease etiology, tumor stage, and type of HCC treatment. Of 3788 HCC patients, 1797 (47.4%) were diagnosed under surveillance, 715 from the US and 1082 from Japan. Patients from the US diagnosed under surveillance had worse liver dysfunction and larger tumor burden than those from Japan. In multivariate analysis, US patients with surveillance-detected HCC had significantly worse survival than those from Japan (HR 1.17, 95% CI 1.00-1.35), which was also observed in propensity-score matched analysis. However, this difference was no longer significant after adjusting for treatment type (HR 1.07, 95% CI 0.92-1.25). When stratified by treatment type, survival was comparable between the two countries except lower survival among patients who underwent resection in the US versus Japan. Prognosis of patients with surveillance-detected HCC is poorer in the US than Japan, primarily driven by differences in treatment delivery. Studies are necessary to elucidate reasons for these differences.

S3552 A Presentation of a Follicular Lymphoma Incidentally Found in the Duodenum

INTRODUCTION: Duodenal lymphomas are considered a rare etiology in the GI tract and are found incidentally in around one out of every 5000 EGDs. These tumors are distinct from nodal follicular lymphomas but share some morphologic, immunochemical, and histological features. Further staging is performed via CT scan, PET scan for classification of the tumor burden of the disease. We present a case presentation of 63 year old male who had a de-novo formation of a duodenal follicular lymphoma. CASE DESCRIPTION/METHODS: 63 yo Caucasian male with PMHx significant for GERD, colon polyps on previous colonoscopy who presented to an outpatient office for evaluation of GERD and follow-up appointment. On the physical exam, the patient's abdominal exam was benign and no additional blood work was performed on admission. During endoscopic evaluation, a nodularity was noted in the second part of the duodenum that was biopsied with cold forceps and biopsies were performed in the antrum to rule out H. Pylori. EGD findings were consistent with esophagitis, gastritis and an irregular Z line at the E/G junction. He was diagnosed with Barrett's esophagus without dysplasia. Pathology results from the nodularity in the second part of the duodenum was found to show small intestinal mucosa with few atypical lymphoid follicles and lymphoid aggregates within the mucosa and lamina propria. Immunohistological stains were performed and were found to be positive for CD20, CD10, and BCL2. Morphological findings were consistent with follicular type B cell lymphoma. Fish testing for BCL2/IGH was performed and a BCL2/IGH gene rearrangement was detected. Upon further discussion with his oncologist, the patient pursued active surveillance of his disease as the PET scan was negative for large tumor burden. Patient was classified as having stage 1E local regional follicular lymphoma and was rescheduled for an endoscopy in about 6 months with no need for chemotherapy or radiation at this time. DISCUSSION: This case highlights the necessity for clinicians to consider the indolent course of follicular lymphomas and the rarity of the disease. Therapy is generally not required unless significant symptoms are present or until disease progression. The long-term clinical outcome or relapse rate for duodenal follicular lymphomas are still unclear as there is no analysis of a large population based registry of survival for patients due to the rarity of the disease.Figure 1.: Duodenal Follicular lymphoma stained with hematoxylin and eosin (low power).Figure 2.: Duodenal Follicular lymphoma stained with antibody with CD10.Figure 3.: Duodenal Follicular lymphoma stained with antibody to Bcl-2.

The Pattern of Cervical Lymph Node Metastasis and Risk Factors of Retropharyngeal Lymph Node Metastasis Based on Magnetic Resonance Imaging in Different Sites of Hypopharyngeal Carcinoma.

BackgroundThis study was to determine the patterns of regional lymph node (LN) spread and the risk factors of retropharyngeal lymph node (RPLN) metastasis based on magnetic resonance imaging (MRI) in hypopharyngeal squamous carcinoma (HPC) to improve clinical target volume (CTV) delineation.MethodsA cohort of 326 consecutive patients of HPC in a single institute were retrospectively reviewed. All patients underwent MRI prior to initial treatment, and the diagnosis based on MRI of the LN metastasis was confirmed by all radiation oncologists in the head and neck group during twice weekly chat rounds. Statistical analysis of data was using chi-square test and multivariant logistic regression model in SPSS 22.0 software.ResultsThe LN metastasis rate of all patients in this cohort was 90.5% (295/326). Level IIa/b and level III were the most frequently involved regions followed by level IV and retropharyngeal region. Skip metastasis only occurred in 6.4% (19/295). Univariate and multivariate analysis demonstrated that primary tumor subsites were located in the posterior pharyngeal wall (P=0.002), bilateral cervical LN metastasis (P=0.020), larger volume of primary gross target (GTVp, P=0.003), and larger volume of LN gross target (GTVnd, P=0.023) were significantly associated with RPLN metastasis.ConclusionThe regional LN spread of HPC follows an ordered pattern as level II is the most frequently involved area followed by level III, level IV, and RPLN. RPLN metastasis is more likely to occur in patients with primary site of posterior pharyngeal wall, large tumor burden, or bilateral neck LN metastasis. Therefore, it is highly recommended that the RPLN should be included into CTV for patients who have these risk factors.

Phase II Clinical Trial of Pembrolizumab in Patients with Progressive Metastatic Pheochromocytomas and Paragangliomas.

Metastatic pheochromocytomas and paragangliomas (MPPGs) are rare endocrine malignancies that are associated with high rates of morbidity and mortality because of their large tumor burden and location, progression, and release of catecholamines. Systemic therapies for MPPGs are limited. MPPGs are characterized by pseudohypoxia that may prevent immune system recognition. We conducted a phase II clinical trial of pembrolizumab in patients with progressive MPPGs. The primary endpoint was the non-progression rate at 27 weeks. The secondary endpoints included the objective response and clinical benefit rates, progression free and overall survival duration, and safety. We also determined whether PDL-1 expression and the presence of infiltrating mononuclear inflammatory cells in the primary tumor were associated with clinical response and hereditary background. Eleven patients were included in this trial, four (36%) with germline mutations and seven (64%) with hormonally active tumors. Four patients (40%, 95% confidence interval (CI) 12–74%) achieved the primary endpoint. The objective response rate was 9% (95% CI: 0–41%). The clinical benefit rate was 73% (95% CI: 39–94%). Four patients had grade 3 adverse events related to pembrolizumab. No patients experienced grade 4 or 5 adverse events or a catecholamine crisis. Progression free survival time was 5.7 months (95% CI: 4.37—not reached). The median survival duration was 19 months (95% CI: 9.9—not reached). PDL-1 expression and the presence of infiltrating mononuclear inflammatory cells in the primary tumor did not seem to be associated with disease response. Single-agent pembrolizumab has modest treatment efficacy in patients with progressive MPPGs. Positive responses seemed to be independent of patients’ hereditary backgrounds, tumor hormonal status, and the presence of infiltrating mononuclear inflammatory cells or PDL-1 expression in the primary tumor.

Abstract 1124: Discordance between gross and histologic findings in progestin-treated endometrial neoplasia

Abstract Introduction: Hysterectomy with or without lymphadenectomy remains the first line of therapy for endometrial cancer (EC). Rising levels of obesity coupled with a trend toward delayed childbearing has led to an increasing population of young women with EC who are poor surgical candidates due to obesity or desire fertility preservation. Accordingly, progestin-based therapy is gaining momentum nationally. Nevertheless, some patients ultimately undergo surgery. Progestin-treated EC can undergo marked stromal decidualization. We hypothesized that this treatment effect may create the false impression of a large residual endometrial tumor burden at the time of gross intra-operative tumor assessment (ITA). As ITA can guide the decision to pursue lymphadenectomy and/or oophorectomy, particularly in community hospitals, familiarity with the gross findings in this setting is essential in order to inform optimal patient management. Methods: 12 hysterectomy specimens with reported progestin-related changes following a diagnosis of atypical hyperplasia or FIGO grade 1-2 EC were identified over a 10-year period. Patient age, duration of progestin therapy, and gross tumor size were recorded. Tumors were histologically assessed for the extent to which decidualized stroma comprised grossly identified lesions and were categorized as having minimal (&amp;lt;10%), intermediate (10-50%), or extensive (&amp;gt;50%) stromal decidualization. Results: Patients' ages ranged from 28-59 years of age (median 41.5 years). 8 were premenopausal and 4 were postmenopausal. Indications for progestin therapy included fertility preservation and a bridge to surgery in patients not desiring fertility. Duration of therapy ranged from 17-332 days (median 80 days). Grossly visible lesions were described in all cases with a median size of 4.1 cm (range 1-8.2 cm). The decidual component was minimal in 3 cases, intermediate in 4 cases, and extensive in 5 cases. 2 cases with grossly visible lesions (2.2 &amp; 7 cm in size) had only focal residual hyperplasia. Extensive decidualization was more common in premenopausal (median 65%, range 10-90%) than in postmenopausal women (median 18%, range 10-40%; p=0.06), irrespective of time on progestin therapy (102.5 vs. 80 days, p=0.87). Conclusions: Large mass lesions following progestin therapy may histologically consist primarily of decidualized stroma with little to no residual neoplastic disease. In these cases, the perceived tumor size does not reflect the actual residual tumor burden; this effect appears to be more pronounced in pre-menopausal patients. In the setting of intraoperative decision-making based on gross tumor assessment, this discrepancy between gross and histologic findings may lead to unnecessary lymphadenectomy and its associated morbidity. Citation Format: Yang Hu, Ahmed N. Al-Niaimi, Alain P. Cagaanan, Paul Weisman, Stephanie M. McGregor. Discordance between gross and histologic findings in progestin-treated endometrial neoplasia [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 1124.

Development of an artificial antibody specific for HLA/peptide complex derived from cancer stem-like cell/cancer-initiating cell antigen DNAJB8

BackgroundPeptide-vaccination therapy targeting tumour-associated antigens can elicit immune responses, but cannot be used to eliminate large tumour burden. In this study, we developed a therapeutic single-chain variable-fragment (scFv) antibody that recognises the cancer stem-like cell/cancer-initiating cell (CSC/CIC) antigen, DNAJB8.MethodsWe screened scFv clones reacting with HLA-A24:20/DNAJB8-derived peptide (DNAJB8_143) complex using naive scFv phage-display libraries. Reactivity and affinity of scFv clones against the cognate antigen were quantified using FACS and surface plasmon resonance. Candidate scFv clones were engineered to human IgG1 (hIgG1) and T-cell-engaging bispecific antibody (CD3xJB8). Complement-dependent cytotoxicity (CDC) and bispecific antibody-dependent cellular cytotoxicity (BADCC) were assessed.ResultsscFv clones A10 and B10 were isolated after bio-panning. Both A10-hIgG1 and B10-hIgG1 reacted with DNAJB8-143 peptide-pulsed antigen-presenting cells and HLA-A24(+)/DNAJB8(+) renal cell carcinoma and osteosarcoma cell lines. A10-hIgG1 and B10-hIgG1 showed strong affinity with the cognate HLA/peptide complex (KD = 2.96 × 10−9 M and 5.04 × 10−9 M, respectively). A10-hIgG1 and B10-hIgG1 showed CDC against HLA-A24(+)/DNAJB8(+) cell lines. B10-(CD3xJB8) showed superior BADCC to A10-(CD3xJB8).ConclusionWe isolated artificial scFv antibodies reactive to CSC/CIC antigen DNAJB8-derived peptide naturally present on renal cell carcinoma and sarcoma. Immunotherapy using these engineered antibodies could be promising.

US–Japan Comparison of Hepatocellular Carcinoma Detected Under Surveillance

Background: Differences in outcomes of hepatocellular carcinoma (HCC) between countries have been largely attributed to variation in the conduct of surveillance and subsequent HCC treatment eligibility; however, differences in outcomes among those detected under surveillance have not been well described. We compared characteristics and prognosis between patients with surveillance-detected HCC from the United States (US) and Japan. Methods: Patients in whom initial HCC was detected under surveillance between January 2006 and December 2015 from two centers in the US and two from Japan were included. Survival was compared between patients from the US and Japan using multivariable Cox regression analysis and propensity-score matched analysis. We performed subgroup analyses by liver disease etiology, tumor stage, and type of HCC treatment. Findings: Of 3788 HCC patients, 1797 (47.4%) were diagnosed under surveillance –715 from the US and 1082 from Japan. Patients from the US diagnosed under surveillance had worse liver dysfunction and larger tumor burden than those from Japan. In multivariate analysis, US patients with surveillance-detected HCC had significantly worse survival than those from Japan (HR 1.17, 95%CI 1.00–1.35), which was also observed in propensity-score matched analysis. However, this difference was no longer significant after adjusting for treatment type (HR 1.07, 95%CI 0.92–1.25). When stratified by treatment type, survival was comparable between the two countries except lower survival among patients who underwent resection in the US versus Japan. Interpretation: Prognosis of patients with surveillance-detected HCC is poorer in the US than Japan, primarily driven by differences in treatment delivery. Studies are necessary to elucidate reasons for these differences. Funding Statement: No funding on this study. Dr. Singal’s research is in part supported by U01CA230694. Dr. Parikh’s research is in part supported by U01CA230669. Declaration of Interests: Hidenori Toyoda has received lecturer fees from Gilead Sciences, AbbVie, MSD, and Bayer. Neehar Parikh has served as a consultant for Bristol Myers-Squibb, Exact Sciences, Eli Lilly, Freenome has served on advisory boards of Genentech, Eisai, Bayer, Exelixis, Wako/Fujifilm and has received research funding from Bayer, Target Pharmasolutions, Exact Sciences, and Glycotest. Amit Singal has been on advisory boards and served as a consultant for Wako Diagnostics, Roche, Exact Sciences, Glycotest, Genentech, Bayer, Eisai, BMS, Exelixis, Merck, AstraZeneca, and TARGET Pharmasolutions. The other authors have no conflict of interest. Ethics Approval Statement: This study was conducted after approval by the institutional review board of each participating institutions and was carried out in compliance with the Helsinki Declaration. Written informed consent was waived due to the retrospective nature of this study.

Abstract IA05: Molecular analysis of exceptional response in high-grade serous ovarian cancer

Abstract A majority of patients with high-grade serous ovarian cancer (HGSC) develop progressive disease following primary treatment, with a five-year survival rate of approximately 40%, and less than 10% survive more than 10 years. Profound genomic instability, treatment with DNA-damaging drugs, and a large tumor burden promote the development of acquired resistance in a large proportion of patients, including multiple convergent resistant events within individuals. Despite the propensity of HGSC to develop drug resistance, a small proportion of patients with advanced disease at diagnosis become long-term survivors. These exceptional patients include those who had suboptimal surgical clearance, and therefore were not cured surgically, and others who have had no evidence of disease recurrence following initial surgery and adjuvant chemotherapy. Our study, which is part of the international collaborative Multidisciplinary Ovarian Cancer Outcomes Group (MOCOG), seeks to identify molecular, immunologic, and epidemiologic factors that influence long-term survival in HGSC. This presentation describes our genomic and immunologic analysis of exceptional survival of this deadly disease. Patient characteristics and clinical histories were evaluated to identify patients diagnosed with advanced stage (Stage IIIC/IV) and histopathologically confirmed HGSC with greater than 10-year overall survival. Whole-genome sequencing (WGS) was performed on primary tumors (median 78x coverage) and germline samples (median 39x coverage) of 55 long-term survivors. Primary tumor samples were also characterized by RNA sequencing, DNA methylation profiling, and immunohistochemistry. Thirty-eight (69%) of long-term surviving patients had residual disease following surgery, suggestive of highly chemosensitive disease. Most patients (41, 75%) were alive at last follow-up and 26 (47%) were progression free. Somatic mutation burden was higher in primary tumors of long-term survivors relative to controls. Genome-wide mutational signatures were predominantly Signature 3 (associated with homologous recombination deficiency), Signature 1 (age related), and Signatures 5, 8, and 16 (unknown etiology). Inactivation of the tumor suppressor RB1 by structural rearrangements or homozygous deletion was frequent in long-term survivors, with 33% of tumors showing associated loss of RB1 protein expression by immunohistochemistry compared to 13% of unselected HGSC controls (n=207; P = 0.001). In an independent HGSC cohort (n=847), RB1 protein loss was associated with prolonged survival (HR: 0.75, P &amp;lt; 0.001) compared to patients with RB1-positive tumors. Furthermore, co-occurrence of germline mutations in BRCA1 or BRCA2 and RB1 loss was associated with a significantly longer overall survival compared to patients with retained RB1 protein expression and no germline BRCA mutation (HR: 0.44, P &amp;lt; 0.001). Multiplexed immunohistochemical analysis with immune cell panels demonstrated distinct associations with long-term survivors. This study delineates the full landscape of genomic alterations in HGSC of long-term survivors. Our findings indicate that specific mutations are associated with enhanced host immune responses and long-term survival. Citation Format: Dale Garsed, Ahwan Pandey, Sian Fereday, Kathryn Alsop, Maartje Wouters, Flurina Saner, Catherine Kennedy, Celeste Pearce, Malcolm Pike, Susan Ramus, Martin Kobel, Anna deFazio, Ellen Goode, Brad Nelson, David Bowtell. Molecular analysis of exceptional response in high-grade serous ovarian cancer [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 IA05.

Optimal strategy of systemic treatment for unresectable pancreatic neuroendocrine tumors based upon opinion of Japanese experts

Background/objectivesA number of therapeutic agents have been reported to be clinically useful for the management of the patients with unresectable pancreatic neuroendocrine tumors (PanNETs) including somatostatin analogues, molecular-targeted agents and cytotoxic agents. However, the optimal strategy for selection among those treatment modalities above in these patients has remained unexplored. MethodsJapanese experts for PanNET discussed and determined the optimal treatment strategies according to the results of previously reported studies. ResultsThe tumor volume of liver metastases and the Ki-67 labeling index were unanimously accepted as indicators of the tumor burden and tumor aggressiveness, respectively, which are two most clinically pivotal factors for determining the strategy of systemic treatment for unresectable PanNETs. In addition, for those with a relatively small tumor burden and slow disease progression, somatostatin analogues were selected as the first-line treatment agents. For those with a relatively large tumor burden and rapid tumor progression, cytotoxic agents were selected, possibly aiming at tumor shrinkage. For those of intermediate tumor volume and/or growth rate, molecular-targeted agents were selected as the first choice. Based on this strategy discussed among the experts, we tentatively prepared a MAP for proposing optimal treatment strategy and examined its validity in some patients with unresectable PanNETs. Results validated the usefulness of this MAP proposed for patients harbouring unresectable PanNETs. ConclusionWe herein propose a tentative MAP for optimal treatment selection for the patients harbouring unresectable PanNETs. Further large scale studies are, however, warranted to validate the usefulness of this MAP proposed in this study.

Abstract A24: Development of a survivable thoracic neuroblastoma mouse model for the study of the extra-adrenal tumor microenvironment

Abstract Neuroblastomas arise from neural crest cells of the paraspinal ganglia and the adrenal medulla, leading to heterogeneity in tumor presentation and location. Outcomes remain poor despite intensified multimodality treatment strategies. Primary tumor site is an independent predictor of survival in all risk groups independent of MYCN amplification status. Adrenal tumors have the worst outcomes; thoracic and cervical tumors carry a more favorable prognosis. We hypothesized that factors specific to the adrenal microenvironment enhance tumor invasion and metastasis. To identify factors that account for the survival differential of neuroblastoma based on primary tumor site, we queried the publicly available national database (TARGET) of human neuroblastoma tumors. 1,076 tumors were categorized by primary tumor site. Children with thoracic tumors had a much more favorable outcome than adrenal primary tumors. Gene expression patterns were significantly different between tumor sites for the 229 patients with microarray data. In general, upregulated genes in the thorax were associated with improved survival, and those in the adrenal gland with poor survival. Enrichment clustering revealed most genes differentially expressed were related to cell-cell junctions. We developed a model system for the study of extra-adrenal neuroblastoma. Luciferin-tagged 9464D neuroblastoma cells suspended in Matrigel were injected into the subpleural space in the left posterior chest of C57/Bl6 mice after thoracotomy. In the comparison group, 9464D cells were injected into the left adrenal gland as previously described in the literature. Mice were imaged weekly using IVIS. Solid tumors developed in the thoracic cavity at the same rate and efficiency as in the adrenal as early as one week following surgery. The survival rate from the surgery is equivalent, though the physiologic tolerance for large tumors after three weeks was lower in the thorax group. The human end point due to large tumor burden was 4 weeks for thoracic implants, compared to 6 weeks for adrenal. Our model makes it possible for the first time to investigate the distinct tumor microenvironments of the adrenal gland and the posterior mediastinum. Using our innovative mouse model, future studies will investigate the role of the differentially expressed genes in tumorigenesis, particularly those related to the cytoskeleton and cell-cell adhesion. Identification of the mechanisms by which cell adhesion molecules affect neuroblastoma initiation, growth, and metastasis in different tumor locations will help explain the differences in clinical outcomes between groups and will open innovative new avenues for therapeutic targeting. Citation Format: Christa N. Grant, Lidan Sun, Zhenqiu Liu, Hong-Gang Wang. Development of a survivable thoracic neuroblastoma mouse model for the study of the extra-adrenal tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr A24.

SAT-131 Asymptomatic Severe Hypoglycemia with Lactic Acidosis in a Case of Non-Hodgkin’s Lymphoma - an Unusual Phenomenon of Hyper-Warburgism

INTRODUCTIONHypoglycemia in malignancy is well known with several etiologies; impaired liver function, insulin receptor autoantibodies, production of insulin-like substance by malignant cells or large tumor burden. Another possible mechanism is the Warburg effect where metabolism shifts towards glycolytic pathways over oxidative phosphorylation even under aerobic conditions leading to excess lactate production. This leads to glucose consumption due to shunting of glucose away from normal cells to cancer cells. Very few cases of lactic acidosis and severe hypoglycemia in Non-Hodgkin’s Lymphoma have been described in the literature. We report such an unusual case here.CASE DISCUSSIONA 52-year-old, African-American male was admitted for severe malnutrition with 80 lb. weight loss, severe hypoglycemia and progressively increasing right chest wall mass. On arrival, he had no classic symptoms of hypoglycemia. Physical exam revealed persistent tachycardia, white patches on oral mucosa and posterior tongue, and an indurated mass on right chest wall with extensive swelling of right upper limb. Lab work was significant for blood glucose (BG) of 41 mg/dL (60–100), lactate 16 mmol/L (0.5 to 2), anion gap 26 mEq/L (3–10), albumin 2.3 g/dL (3.4 to 5.4) and normal renal and liver function tests. Fingerstick sugar readings were persistently in the 20s with no response to multiple boluses of dextrose and glucagon. He was started on dextrose 5% (D5) drip and intravenous solumedrol. Solumedrol was weaned off and D5 titrated down to investigate causes of hypoglycemia. BG dropped to 39 and corresponding labs showed insulin level of < 2 mcUnit/mL (2–20), C-peptide of 0.2 ng/mL (0.8–6.0) and ketone level of 0.2 mmol/L (<0.4). IGF-1 and IGF-2 were both low at 26 ng/mL (61–200) and 113 ng/mL (333–967) respectively. A CT torso with contrast showed bilateral pleural effusions, moderate pericardial effusions and a large ill-defined heterogeneous mass along anterior chest wall. He underwent ultrasound guided biopsy of the chest wall mass and diagnosed with diffuse large B-cell lymphoma. He also tested positive for HIV/AIDS and Hepatitis C. PET scan showed diffuse FDG (fluorodeoxyglucose) uptake consistent with advanced disease. He was started on chemotherapy and lactate and BG normalized soon after 1st cycle.CONCLUSIONIn our case; suppressed insulin, low C-peptide and IGF-2 levels indicate non-insulin mediated hypoglycemia due to rapid glucose utilization by cancer cells. Severe hypoglycemia with lack of neuroglycopenic symptoms suggests use of lactate (rather than glucose) as an alternative metabolic fuel for brain, thus preserving its function. Our patient presented with an exaggerated Warburg effect (hyper-Warburgism) as evident by extreme glucose consumption, severe lactic acidosis and large tumor burden on FDG/PET. Chemotherapy must be instituted timely to correct these abnormalities.

Impact of Paranasal Sinus Invasion on Oncologic and Dosimetric Outcomes in Nasopharyngeal Carcinoma Following Intensity-Modulated Radiation Therapy-Implications for Risk Stratification and Planning Optimization.

Purpose: This study aims to investigate the prognostic value and dosimetric impact of paranasal sinus invasion (PSI) in patients with nasopharyngeal carcinoma (NPC), and further to explore the feasibility of an integrative prognostic model based on anatomic, volumetric, and dosimetric features.Methods: Two hundred six patients with T3 NPC receiving intensity-modulated radiation therapy (IMRT) were retrospectively analyzed. Dosimetric parameters were calculated from dose–volume histograms. Primary gross tumor volume (GTV-P) and dosimetric parameters were categorized using optimal cutpoints determined by R. Local recurrence-free survival (LRFS) was estimated using Kaplan–Meier method. Independent risk factors for LRFS were identified through univariable and multivariable analyses by Cox proportional hazards models.Results: The incidence of PSI was 10.7% (22/206). Patients with PSI had significantly inferior 5-year LRFS (77.3 vs. 93.8%, P = 0.006). IMRT plans for patients with PSI had larger dose heterogeneity, higher frequency of underdosing, and higher maximum dose to optic structures. When categorized by optimal cutpoints, GTV-P > 38.67 cm3 (5-year LRFS, 84.8 vs. 97.4%, P = 0.008), and V66.88 < 89.87% (5-year LRFS, 67.1 vs. 94.5%, P < 0.001) were associated with significantly worse local outcome. Multivariable analyses showed that PSI, GTV-P > 38.67 cm3, and V66.88 < 89.87% were independent risk factors for local relapse, either in patients with or without concurrent chemotherapy. An integrative prognostic model was then established upon the cumulative score of risk factors. Subgroups with score of 0, 1–2, and 3 had distinctive local outcomes; the 5-year LRFS was 96.6, 84.7, and 58.3%, respectively (P < 0.001).Conclusions: Paranasal sinus invasion jeopardized local control in T3 NPC patients due to large tumor burden and inadequate radiation dose in GTV-P. The presence of PSI, GTV-P, and radiation underdosing combined are critical for the risk stratification of local failure.

Alarmin-painted exosomes elicit persistent antitumor immunity in large established tumors in mice

Treating large established tumors is challenging for dendritic cell (DC)-based immunotherapy. DC activation with tumor cell-derived exosomes (TEXs) carrying multiple tumor-associated antigen can enhance tumor recognition. Adding a potent adjuvant, high mobility group nucleosome-binding protein 1 (HMGN1), boosts DCs’ ability to activate T cells and improves vaccine efficiency. Here, we demonstrate that TEXs painted with the functional domain of HMGN1 (TEX-N1ND) via an exosomal anchor peptide potentiates DC immunogenicity. TEX-N1ND pulsed DCs (DCTEX-N1ND) elicit long-lasting antitumor immunity and tumor suppression in different syngeneic mouse models with large tumor burdens, most notably large, poorly immunogenic orthotopic hepatocellular carcinoma (HCC). DCTEX-N1ND show increased homing to lymphoid tissues and contribute to augmented memory T cells. Importantly, N1ND-painted serum exosomes from cancer patients also promote DC activation. Our study demonstrates the potency of TEX-N1ND to strengthen DC immunogenicity and to suppress large established tumors, and thus provides an avenue to improve DC-based immunotherapy.

The effects of UVB irradiance on vitiligo phototherapy and UVB-induced photocarcinogenesis.

Phototherapy is the most commonly used modality for repigmenting vitiligo. Currently, UVB emitting devices, including narrow-band UVB (NBUVB) and excimer laser/light, are considered as the treatment of choice. While emitting wavelengths at close proximity, excimer lights emit higher irradiance (HI; W/m2 ) compared to NBUVB. Clinical reports have shown that excimer light is more efficacious in treating vitiligo compared to NBUVB, and we demonstrated that irradiance plays a critical role in promoting melanoblasts differentiation. UVB radiation from the sun is closely associated with photocarcinogenesis of the skin. Sunscreens were used to protect the skin by reducing UVB irradiance (low irradiance (LI) UVB). Sunscreen use was associated with skin cancer reduction in clinical trials. Paradoxically, sunscreen use was associated with increased sunburn episodes in the real-world settings. It was shown that UVB-induced sunburn depends on fluence (J/m2 ) but not irradiance of UVB radiation. We investigated the significance of irradiance in the context of UVB-induced carcinogenesis of the skin. For mice receiving equivalent fluence of UVB exposure, the LIUVB-treated mice showed earlier tumor development, larger tumor burden, and more epidermal keratinocytes harboring mutant p53 as compared to their HIUVB-treated counterparts. These results suggested that at equivalent fluence, LIUVB radiation has more photocarcinogenic potential on the skin compared to its HI counterpart. Since development of sunburn with or without sunscreen use indicates that certain threshold of UVB fluence has been received by the skin at LI and HI, respectively, sunburn episodes with sunscreen use (LIUVB) are more damaging to the skin compared to that without sunscreen (HIUVB) application. In summary, since irradiance plays an important role determining the biological effects of UVB radiation on the skin, future related studies should take this critical parameter into consideration.

Development of a novel murine model of lymphatic metastasis.

Current laboratory models of lymphatic metastasis generally require either genetically modified animals or are technically challenging. Herein, we have developed a robust protocol for the induction of intralymphatic metastasis in wild-type mice with reproducible outcomes. To determine an optimal injection quantity and timeline for tumorigenesis, C57Bl/6 mice were injected directly into the mesenteric lymph duct (MLD) with varying numbers of syngeneic murine colon cancer cells (MC38) or gastric cancer cells (YTN16) expressing GFP/luciferase and monitored over 2-4 weeks. Tumor growth was tracked via whole-animal in vivo bioluminescence imaging (IVIS). Our data indicate that the injection of tumor cells into the MLD is a viable model for lymphatic metastasis as necropsies revealed large tumor burdens and metastasis in regional lymph nodes. This protocol enables a closer study of the role of lymphatics in cancer metastasis and opens a window for the development of novel approaches for treatment of metastatic diseases.

Cord Blood Regulatory T Cells Do Not Impair Anti-Myeloma Effect of Conventional T Cells

Introduction Regulatory T cells (Tregs) are potent immunosuppressors and, specifically, cord blood (CB) Tregs are emerging as a promising treatment for graft vs. host disease as well as immune mediated bone marrow failure disorders. We and others have shown that when compared to peripheral blood (PB), CB Tregs have a higher expression of Helios, a marker of thymic Tregs; exert superior suppression on proliferating conventional T cells (Tcons) and do not secrete inflammatory IL-17 or express RORүt under stressful conditions. Such a stable suppressor profile coupled with their ready availability as an off-the-shelf product positions CB Tregs to be a very attractive therapeutic agent. Multiple myeloma, a plasma cell clonal malignancy, has been incurable and required more effective and safer therapy. Objectives We hypothesized that adoptive therapy with CB Tregs might not interfere with the anti-myeloma activity and relieve the adverse effects related to the excess immune response during the immune therapy. Methods NOD-SCID IL2rγnull (NSG) mice were used to first establish the myeloma tumor model, where mice were injected intravenously via tail vein with 3 × 106 GFP-Firefly luciferase labeled MM.1S cells. For generating CB Tregs, Treg cell enrichment was performed from the whole CB unit using CD25+ magnetic beads followed by continuous culture in the presence of CD3/28 T-cell activator beads, and human recombinant interleukin-2 for 14 days. To assess the CB Tregs impact on anti-myeloma effect by Tcons, the mice inoculated MM.1S cells were injected with 5 × 106 PB CD3+Tcons on day 14 with or without 10 × 106 ex-vivo expanded CB Tregs on day 16, 23, and 30. CB Tregs alone arm was also set up to assess the CB Tregs impact on myeloma progression. The progression of MM.1S cells was monitored by in vivo bioluminescence imaging (BLI). Results The expanded CB Tregs showed a consistent phenotype of CD4+25+127- FoxP3high and more than 80% suppression of the proliferating CD4+ Tcons in vitro. Tcons with or without CB Tregs regressed the myeloma cells in the mice while CB Tregs alone did not have any impact. Notably, the relapse was slightly delayed in the Tcons with CB Tregs recipients compared to the Tcons alone (Figure A). Although CB Tregs recipients died due to graft vs host disease eventually, the survival was not inferior to that in the Tcons alone (Figure B). Upon euthanasia, myeloma cells were barely detectable in the both arms of Tcons with or without CB Tregs compared to large tumor burden in the control arm. Of note, extramedullary tumor was seen in the Tcons alone arm (Figure C). Conclusions Our results demonstrate that ex-vivo expanded CB Tregs do not impair, rather might enhance, the anti-myeloma activity of Tcons in a xenogenic model. These data provide additional insight of the Tregs new role in the tumor environment and may contribute to the development of the novel immunotherapies in the future.

P844 A stroke of bad fortune

Abstract Case description We report the case of a 78 year old man who was referred to our hospital following identification of an intracardiac mass on transthoracic echocardiogram (TTE). The study was for work-up of a recent left middle cerebral artery thromboembolic stroke, with successful endovascular clot retrieval. His only other active medical issue was metastatic prostate cancer with bony involvement, on palliative hormone therapy with a well controlled prostate specific antigen level. He was an ex-smoker and and had an ECOG performance status of zero. On physical examination, the patient was clinically well, with unremarkable cardiopulmonary auscultation. The TTE demonstrated an echodense mass in the left atrium (LA), with Doppler colour giving a suggestion of its size (image A). The subsequent transoesophageal echocardiogram illustrated a large, well defined, heterogenous, echodense mass dominating the LA (image B). It was not adherent to the interatrial septum. There was no significant spontaneous echocontrast or thrombus formation in the left atrial appendage (LAA). Considering the location of the mass, the presumptive diagnosis of atrial myxoma was less likely. Differential diagnoses we considered included pure thrombus, infection and benign or malignant cardiac tumours. It was unlikely that this patient had a pure thrombus only considering the LAA was clear. He also did not have any non-specific or focal clinical features suggestive of infection. The patient went on to have a gated CT thoracic aortogram, which showed a contrast-enhancing soft tissue mass within the LA measuring approximately 50x40 millimetre, which invaded into the left inferior pulmonary vein, and was contiguous with a soft tissue mass in the left lower lobe of the lung (image C). He also had a positon emission tomography scan, which showed the highly metabolically active mass in the lung invading into the left inferior pulmonary vein, and as well as left atrium (image D). The patient underwent a biopsy of this left lower lung lesion, which confirmed squamous cell carcinoma of lung origin. Due to the large tumour burden in the LA, the joint decision with medical and radiation oncology teams, was not to administer systemic chemo- or localised radiotherapy, as this would lead to high risk of tumour embolisation. The patient also had a short period of therapeutic anticoagulation with intravenous unfractionated heparin to treat the likely thrombotic coating to the left atrial tumour extension, but developed a retroperitoneal haematoma, and hence anticoagulation was ceased. The patient was referred to palliative care services, and returned back to the community. Conclusion Cardiac tumours, whether primary or secondary, are rare. They are most frequently identified on post-mortem examination. This case is unusual, in that the patient had a second primary tumour and has remained completely asymptomatic prior to embolic presentation, despite the large size of the mass. Abstract P844 Figure 1.