Cholangiocarcinomas are rare tumors originating at any point along the biliary tree. These tumors often pose significant challenges for diagnosis and treatment, and often carry a poor prognosis. However, in recent years, studies have identified significant molecular heterogeneity with up to 50% of tumors having detectable mutations, leading to the guideline recommendations for molecular testing as part of the diagnostic workup for these tumors. In addition, better classification of these tumors and understanding of their biology has led to new drugs being approved for treatment of this resistant tumor. This manuscript will provide a comprehensive review of the epidemiology, risk factors, diagnostic approach, molecular classification, and treatment options for patients with advanced cholangiocarcinomas.

Background: Chemoradiation with curative intent in older adults with locally advanced head and neck squamous cell carcinoma (HNSCC) has been a challenge, because of its potential toxicities.Methods: We selected primary HNSCC cases from the SEER-Medicare linked database, assessed overall survival (OS) and adverse events and their associations with different treatments, across four age groups including the youngest (66-69 years) and the oldest (≥80 years).Results: Better OS was associated with chemoradiation compared to radiation alone, not only in all patients (N = 5879) (hazard ratio [HR] = 0.82, p < 0.001), but also in the oldest group (N = 1380) (HR = 0.77, p = 0.006) in whom the adverse events rates were not higher than those in the youngest (N = 1562); more of the latter (26%-30%) than the former (14%-19%) received chemoradiation, regardless of their comorbidity indices. Conclusions: Our findings provide evidence that patients' characteristics, other than chronological age, should be equally considered in selecting the best therapy for older patients with HNSCC.

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723 Background: Active modification of surrounding stroma is a critical mechanism of tumor cell growth in pancreatic ductal adenocarcinoma (PDAC). There is some early translational evidence that losartan (L) and vitamin D (D) may affect the tumor microenvironment and supportive stroma in PDAC to help restore a physically and biologically tumor-suppressive stroma. These effects of potentially stroma-modifying drugs have not been established in the clinical management of metastatic PDAC (mPDAC), where there have been limited advances in treatment and prognosis remains poor. Methods: This is a single center, retrospective analysis of patients with mPDAC treated at Fox Chase Cancer Center from 2010 to 2019. All data including L and D use were extracted from the medical record. Patient characteristics were compared across subgroups using Chi-square tests, Fisher’s exact tests, and Wilcoxon rank sum tests. The primary outcome was overall survival (OS) from the time of metastatic diagnosis. Kaplan-Meier curves and log-rank tests were used to compare unadjusted OS across subgroups. Cox proportional hazards models were used to characterize OS adjusted for age at metastatic diagnosis, sex, initial stage at diagnosis, performance status, Charlson Comorbidity Index (CCI), hypertension, and renal disease. Results: 518 patients were included; a majority were male (54.1%), White (82.4%), and diagnosed with de novo mPDAC (54.6%). About half of patients had hypertension (53.5%) and few had renal dysfunction (5.6%). 153 (29.5%) patients were taking D and 41 (8%) patients were taking L. Women were more likely to take D than men (p < 0.001) and White patients were more likely to take L than other races/ethnicities (p = 0.006). Median OS since metastatic diagnosis for patients taking L was 11.4 months compared to 9.6 months for patients not taking L (p = 0.07). Median OS for patients taking D was 11.3 months compared to 8.7 months for those not taking D (p = 0.10). A Cox proportional hazards model adjusting for confounders, however, showed that both L (HR 0.66, p = 0.02) and D (HR 0.81, p = 0.04) were significantly associated with improved OS from time of metastatic diagnosis. Conclusions: This large retrospective study demonstrates potential clinical and survival benefit of L and D in conjunction with mPDAC treatment. L and D are safe, well tolerated, and widely used in general medical practice. These results support further investigation of the stroma-modifying potential of L and D, as well as conducting prospective trials with these agents to further validate these findings.

We have focused on a protein kinase called PBK or TOPK, believed to be an intermediate in the Ras - MAP Kinase signaling cascade which is implicated in malignant cell growth,. PBK was originally identified in our laboratory as a differentially expressed gene in Burkitt’s lymphoma cells as compared to hyperplastic tonsillar B cells. PBK protein expression was detected in 9 out of 12 primary AML samples, 3 out of 3 ALL samples and one sample each of plasmacytoma and blastic-type Mantle cell lymphoma that were analyzed. We demonstrated inhibition of p38 MAPK phosphorylation utilizing an inducible construct involving dominant negative PBK mutant in 293 cells. Homology with the MAP Kinase Kinase, MKK3, protein- protein interactions with c-Raf and its observed effect on p38 MAP Kinase suggest that PBK possibly functions as a MAP Kinase Kinase which utilizes p38 MAP Kinase as a downstream phosphorylation target. Presently, the regulation and function of PBK have been examined with a goal to elucidate its role in the growth of hematopoietic neoplasms. We have found that under conditions of stymied proliferation of HL60, promyelocytic leukemia cells either by genotoxic drugs e.g doxorubicin or by induction of differentiation with TPA along macrophage pathway, PBK is strongly downregulated while housekeeping proteins like actins remain constant. Accumulation of dephosphorylated ( Tyr15) form of Cdc2 Kinase under treatment with doxorubicin indicated cell cycle arrest at the G2/M boundary. Electrophoretic mobility shift assay (EMSA) has demonstrated the binding of ATF/CREB family of transcription factors upstream of PBK transcription start site. A variety of cell lines derived from multiple tissue origin when analyzed, demonstrated codistribution of PBK and transcription factor CREB indicating that CREB factor may be involved in PBK gene expression. To further analyze the regulatory mechanisms involving PBK gene expression, a 2.5 kb putative promoter for the PBK gene has been amplified utilizing human genomic DNA and cloned next to click beetle red-emitting luciferase coding unit. Preliminary data indicate that 0.6kb promoter containing the CRE element retains significant activity compared to 2.5kb promoter. Assay of luciferase activity utilizing different subfragments of the promoter is underway. Efforts have been made to examine PBK expression following ectopic expression of dominant negative CREB mutants. To that end, stable clones have been isolated from 293, human embryonic kidney cells under neomycin selection. Further experiments to monitor PBK expression by western immunoblot analysis will clarify the role of CREB factors in controlling PBK expression. In order to obtain knock down expression of PBK using inducible shRNA, a 51bp long double stranded oligomer derived from the PBK coding region has been cloned next to the Tet-responsive promoter with an object to study possible function of PBK in tumor cells which express the PBK protein.

496 Background: Hepatocellular carcinoma (HCC) disproportionately affects minorities, particularly Black and Hispanic patients, and patients of lower socioeconomic status. These patients are more likely to be diagnosed with advanced disease, less likely to receive curative therapies, and have higher mortality rates. Data on the impact of disparities on patterns of systemic treatment (STx) in these disadvantaged groups are limited. This retrospective observational study used a large real-world database to explore differences in patient characteristics and patterns of STx based on race/ethnicity (R/E) and insurance status. Methods: 1283 patients diagnosed with HCC from 2011 to 2021 with known race, insurance, documented metastatic disease (mHCC), and without prior transplant from the nationwide de-identified Flatiron Health EHR-derived database were selected and analyzed. Chi-squared tests, T-tests, and log-rank tests were used to assess how R/E and insurance (Medicaid vs non-Medicaid) were related to HCC risk factors, number of lines of systemic therapy (LOT), and time from metastatic diagnosis (mDx) to start of STx. Results: Of 1283 patients evaluated, there were 750 white (W), 175 Black (B), 122 Hispanic (H), 69 Asian (A), and 167 patients with other race. B and H patients had the highest rates of known HCV (B 74.3%, H 48.4%, W 41.2%, A 23.2%; p < 0.001) and A patients were most likely to have known HBV (53.6%). More B and H patients had Medicaid (W 10.9%, A 14.3%, B 18.9%, H 28.5%, p < 0.001) and had the lowest rates of Medicare with commercial insurance (W 25.9%, A 21.7%, B 12.6%, H 14.6%, p < 0.001). H patients had the lowest rates of commercial insurance (H 39.3%, W 41.3%, A 44.9%, B 44.6%, p < 0.001). There was no significant difference in likelihood of receiving approved STx after mDx based on R/E. A patients had the highest rates of receiving multiple LOT (A 37.5%, W 18.5%, B 18.9%, H 20.5%; p = 0.285). 30-40% of patients with mHCC did not receive any STx and only 18-27% received more than 1 LOT. Most patients received STx for mHCC within 2 months without a significant difference based on R/E. There was no difference in unadjusted time to treatment based on insurance. Conclusions: This large-scale analysis did not reveal significant differences in the likelihood of receiving STx after mDx based on R/E or insurance. This analysis has limited data from safety net hospitals, which may impact our ability to fully elucidate disparities in the medical management of advanced HCC. 30-40% of patients with mHCC did not receive any STx and only 18-27% received more than 1 LOT, indicating that a significant portion of patients with HCC may be undertreated even in academic and community practice settings. Large scale real-world database analysis is a critical way to better understand treatment and survival outcomes in this population, which is expected to have the highest rates of HCC over the next 10 years and has been underrepresented in HCC trials.

1557 Introduction: The phosphatidylinositol-3-kinase (PI3K)/Akt signaling pathway controls key cellular processes and is frequently activated in both acute and chronic myeloid leukemia (AML, CML) as well as high-risk MDS, thus representing an attractive therapeutic target. UCN-01 inhibits a number of serine-threonine kinases, including phosphatidylinositide-dependent kinase 1, which phosphorylates and activates Akt. Perifosine, an alkylphospholipid, targets the pleckstrin homology domain of Akt, thereby inhibiting its plasma membrane translocation and activation. Synergistic inhibition of Akt by UCN-01 and perifosine has been demonstrated in prostate and lung cancer cell lines (Clin Cancer Res 10: 5242, 2004). Methods: We conducted a Phase I study to determine the maximum tolerated dose (MTD) and recommended Phase II dose of UCN-01 and perifosine, using a standard 3+3 dose escalation design. Patients (pts) >18 years with poor-risk, or relapsed/ refractory AML or acute lymphoblastic leukemia (ALL), CML in accelerated/blastic phase or MDS failing standard therapy, and peripheral blast count <30×109/l were eligible. Perifosine was administered on day (d)1 at 150 mg orally every 6 hours, then 100 mg daily from d2 continuously. UCN-01 was given as a 3-hour infusion on d4 at one of 3 dose levels (DL) (DL1 40/DL2 65/DL3 90 mg/m2). 28-day cycles were repeated depending on response/tolerability, with UCN-01 given at 50% dose. Antiemetic prophylaxis (perifosine) and hydration (UCN-01) were required. Results: Thirteen pts with AML (11), ALL (1), and MDS (1) were treated (DL1, n=6; DL2, n=4; DL3, n=3). Median age was 69 years (range, 20–85), 77% pts were male, and median number of prior treatments was 3 (range, 1–6). Nine of 11 AML patients had secondary (7)/therapy-related (2) disease, 4 had adverse and 5 intermediate karyotypes, and all were either primary refractory (4) or had first remission duration < 12 months (7). Pts received median 1 (range, 1–3) cycle of therapy. Five pts did not complete 1st cycle due to disease progression (n=3; DL1), cholecystitis/sepsis (n=1; DL3), or drug-related toxicity (n=1; DL3), and 4 received hydroxyurea temporarily to control increasing blast counts. The most frequent drug-related toxicities (NCI CTC v3) were grade (gr) 1/2 nausea and diarrhea (62% each), vomiting (54%), fatigue and hyperglycemia (31% each) anorexia, hypocalcemia and constipation (23% each), increased AST/ALT (15%), hypokalemia and hypotension (8% each). Few ≥gr 3 toxicities were seen, all at DL3: fatigue (gr 3), hyperglycemia (gr 4), hypokalemia (gr 3), pericarditis/tamponade/hypotension (gr 4) and respiratory distress (gr 4). MTD was therefore defined as 65 mg/m2 based on 2 pts with dose limiting toxicities at DL3. One AML pt (DL1) had disease stabilization for 3 cycles and one MDS pt (DL2) had improvement in neutrophil count. Given lack of sufficient evidence of clinical efficacy, the DL2 cohort was not expanded to 6 pts as planned. However, no gr 3/4 drug-related toxicities were observed in 10 pts treated at DL1/2. Pharmacodynamics: Western blot analysis did not consistently demonstrate appreciable direct Akt inhibition in ficolled blood/marrow mononuclear cells from 5 pts (DL1/2) on d4 (perifosine alone) or d21-28, however, a 38–74% reduction in phosphorylated ribosomal protein S6 in leukemic blasts from 3 pts on d4 was noted by intracellular flow cytometry, consistent with inhibition of signaling through the Akt downstream target p70S6 kinase. Pharmacokinetics: The average steady state concentration (Css) of perifosine was 4.75±2.53 μg/mL, consistent with published data (Eur J Cancer 38: 1615, 2002), with 1 pt having an unusually high Css of 9.25 μg/mL. The end-of-infusion concentration for UCN-01 was also consistent with published data (Clin Cancer Res 13: 2667, 2007), with average Cmax 13.2±0.424 μg/mL and 20.7±3.08 μg/mL at doses of 40 and 65 mg/m2, respectively. Conclusion: UCN-01 (40 or 65 mg/m2)/perifosine can be safely administered, but this regimen lacked clinical efficacy. This approach may have failed because of insufficient Akt inhibition in vivo and/or need to inhibit more than one signaling pathway to produce clinical response. Future studies with more potent Akt inhibitors should examine the validity of this approach in conjunction with pharmacodynamic monitoring. Disclosures: Carroll: Glaxo Smith Kline, Inc.: Research Funding; Sanofi Aventis Corporation: Research Funding; TetraLogic Pharmaceuticals: Research Funding; Agios Pharmaceuticals: Research Funding. Gojo:Keryx Inc.: Research Funding. Off Label Use: Neither UCN-01 nor perifosine have an approved indication.