Pancreatic Neck Cancer Research Articles

Interpretation of the surgical treatment of pancreatic cancer of the 2024 edition of the NCCN guidelines

Pancreatic cancer is a highly malignant tumor in the digestive system, and radical surgery is the only possible means to cure pancreatic cancer at present. In the past decade, pancreatic surgery has been developing rapidly, with various new technologies and concepts emerging, among which the use of minimally invasive techniques and the popularization of neoadjuvant therapy concepts are the most notable. At the same time, the surgical treatment of pancreatic cancer still has a long way to go, and many problems need to be solved urgently. This article introduces the surgical treatment of pancreatic cancer in the 2024 edition of the NCCN guidelines, focusing on minimally invasive and open surgical treatments, expanded lymph node dissection, combined vascular resection and reconstruction, surgical treatment of pancreatic neck cancer and neoadjuvant therapy, and briefly discussing the unresolved issues.

Abstract 1414: HBM9014, a first-in-class fully human anti-LIFR antibody with excellent preclinical efficacy and safety profile

Abstract Background: Leukemia inhibitory factor (LIF) and cardiotrophin like cytokine factor 1 (CLCF1) are multi-functional cytokines from IL-6 family. They are reported to be highly expressed in a variety of human cancers such as pancreatic carcinoma, cholangiocarcinoma, NSCLC, GBM, head and neck cancer etc. Their expression is associated with poor prognosis and survival. LIFR is the key component of LIF/CLCF1 receptors. Antibody targeting LIFR has the advantage to block both LIF and CLCF1 pathways thus inhibiting tumor growth more effectively than products to block single cytokines. Methods: Fully human Anti-LIFR antibodies were generated from H2L2 Harbour Mice® transgenic platform. In vitro function of the antibodies was tested for their abilities to block LIF/CLCF1 induced downstream signaling pathway and tumor spheroid proliferation. In vivo efficacy was tested in multiple tumor models as monotherapy and in combination with cisplatin. DRF toxicokinetics was evaluated on NHP with a 4-week repeat-dose toxicity study. Results: HBM9014, a fully human anti-LIFR antibody generated by H2L2 Harbour Mice®, specifically binds LIFR thus blocks the interaction between LIF/CLCF1 and their respective receptors, inhibits downstream STAT3 phosphorylation, and reduces exogenous and endogenous LIF induced tumor spheroid proliferation in vitro. Furthermore, HBM9014 shows potent anti-tumor activity in multiple tumor models in vivo. In a GLP NHP 4-week repeat-dose toxicity study, HBM9014 is well tolerated up to 150 mg/kg with no discernable drug-related toxicity. Conclusions: HBM9014 specifically binds to the key component of LIF and CLCF1 receptor, LIFR, thus blocks both LIF and CLCF1 signaling pathways. HBM9014 shows significant cell proliferation inhibition alone or in combo with small molecule inhibitors in 3D culture of multiple cancer cell lines. It also shows significant in vivo antitumor efficacy as monotherapy, and enhanced efficacy in combination with Cisplatin in multiple mouse models. Importantly, despite the benefits of double blocking, HMB9014 has an excellent safety profile. Taken together, HMB9014 is a promising drug candidate for advanced cancer with favorable efficacy and safety profiles that warrant clinical validation. Citation Format: Jue Zeng, Dongxu Zhang, Louis Liu, Lingbing Zhang. HBM9014, a first-in-class fully human anti-LIFR antibody with excellent preclinical efficacy and safety profile [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1414.

Exosomal lncRNA XIST promotes perineural invasion of pancreatic cancer cells via miR-211-5p/GDNF.

Perineural invasion (PNI) is an essential form of tumor metastasis in multiple malignant cancers, such as pancreatic cancer, prostate cancer, and head and neck cancer. Growing evidence has revealed that pancreatic cancer recurrence and neuropathic pain positively correlate with PNI. Therefore, targeting PNI is a proper strategy for pancreatic cancer treatment. Exosomal lncRNA derived from pancreatic cancer cells is an essential component of the tumor microenvironment. However, whether exosomal lncXIST derived from pancreatic cancer cells can promote PNI and its exact mechanism remains to be elucidated. We show that lncXIST mediates nerve-tumor crosstalk via exosomal delivery. Our data reveal that exosomal lncXIST derived from pancreatic cancer cells is delivered to neural cells and promotes their release of glial-cell-line-derived neurotrophic factor (GDNF), essential in facilitating the PNI of pancreatic cancer. Mechanistically, microRNA-211-5p negatively regulates GDNF, and lncXIST serves as a miR-211-5p sponge. The function of exosomes in the dynamic interplay between nerves and cancer is confirmed in both in vivo and in vitro PNI models. Therefore, targeting pancreatic cancer cell-derived exosomal lncXIST may provide clues for a promising approach for developing a new strategy to combat PNI of pancreatic cancer.

The transformative potential of mRNA vaccines for glioblastoma and human cancer: technological advances and translation to clinical trials.

Originally devised for cancer control, mRNA vaccines have risen to the forefront of medicine as effective instruments for control of infectious disease, notably their pivotal role in combating the COVID-19 pandemic. This review focuses on fundamental aspects of the development of mRNA vaccines, e.g., tumor antigens, vector design, and precise delivery methodologies, - highlighting key technological advances. The recent, promising success of personalized mRNA vaccines against pancreatic cancer and melanoma illustrates the potential value for other intractable, immunologically resistant, solid tumors, such as glioblastoma, as well as the potential for synergies with a combinatorial, immunotherapeutic approach. The impact and progress in human cancer, including pancreatic cancer, head and neck cancer, bladder cancer are reviewed, as are lessons learned from first-in-human CAR-T cell, DNA and dendritic cell vaccines targeting glioblastoma. Going forward, a roadmap is provided for the transformative potential of mRNA vaccines to advance cancer immunotherapy, with a particular focus on the opportunities and challenges of glioblastoma. The current landscape of glioblastoma immunotherapy and gene therapy is reviewed with an eye to combinatorial approaches harnessing RNA science. Preliminary preclinical and clinical data supports the concept that mRNA vaccines could be a viable, novel approach to prolong survival in patients with glioblastoma.

Anti-tumor effects of ketogenic diets and their synergism with other treatments in mice: Bayesian evidence synthesis of 1755 individual mouse survival data

BackgroundKetogenic diets (KDs) are high-fat diets with putative anti-tumor effects. The aim of this study was to synthesize the evidence for the anti-tumor effects of KDs in mice, with a focus on their possible synergism with chemotherapy (CT), radiotherapy (RT), or targeted therapies (TT). MethodsRelevant studies were retrieved from a literature search. A total of 43 articles reporting on 65 mouse experiments fulfilled the inclusion criteria, and 1755 individual mouse survival times were collated from the study authors or the publications. The restricted mean survival time ratio (RMSTR) between the KD and control groups served as the effect size. Bayesian evidence synthesis models were used to estimate pooled effect sizes and to assess the impact of putative confounders and synergism between KD and other therapies. ResultsOverall, there was a significant survival-prolonging effect of KD monotherapy (RMSTR = 1.161 ± 0.040), which was confirmed in meta-regression accounting for syngeneic versus xenogeneic models, early versus late KD start and subcutaneous versus other organ growth. Combining the KD with RT or TT, but not CT, was associated with a further 30% (RT) or 21% (TT) prolongation of survival. An analysis accounting for 15 individual tumor entities showed that KDs exerted significant survival-prolonging effects in pancreatic cancer (all treatment combinations), gliomas (KD + RT and KD + TT), head and neck cancer (KD + RT), and stomach cancer (KD+RT and KD + TT). ConclusionsThis analytical study confirmed the overall anti-tumor effects of KDs in a large number of mouse experiments and provides evidence for synergistic effects with RT and TT.

Pancreaticoduodenectomy with celiac artery resection (PD-CAR) for unresctable locally advanced pancreatic ductal adenocarcinoma

Locally advanced pancreatic ductal adenocarcinoma (LA-PDAC) involving the celiac artery (CeA), the common hepatic artery and the gastroduodenal artery (GDA) is considered unresectable. We developed the novel procedure of pancreaticoduodenectomy with celiac artery resection (PD-CAR) for such LA-PDACs. From 2015 to 2018, we performed curative pancreatectomy with major arterial resection for 13 LA-PDACs as a clinical study (UMIN000029501). Of those, four patients with pancreatic neck cancer involving the CeA and GDA were candidates for PD-CAR. Prior to surgery, blood flow alterations were performed to unify the blood flow to the liver, stomach, and pancreas, resulting in feeding from the cancer-free artery. During PD-CAR, arterial reconstruction of the unified artery was performed as needed. Based on the records of PD-CAR cases, we retrospectively analyzed the validity of the operation. R0 resection was achieved in all patients. Arterial reconstruction was performed in three patients. In another patient, the hepatic arterial flow was maintained by preserving of the left gastric artery. The mean operative time was 669min, and the mean blood loss was 1003ml. Although Clavien-Dindo classification III-IV postoperative morbidities occurred in three patients, no reoperations nor mortalities occurred. Although two patients died of cancer recurrence, one patient survived for 26months without recurrence (died of cerebral infarction), and another is alive at 76months without recurrence. PD-CAR, which enabled R0 resection and preservation of the residual stomach, pancreas, and spleen, provided acceptable postoperative outcomes.

Defining the Cost Variation by Site-of-Care for Radiotherapy: A Claims-Based Analysis

<h3>Purpose/Objective(s)</h3> To understand the qualitative differences in total cost of care between sites of care (SOC) in patients undergoing radiation therapy (RT). <h3>Materials/Methods</h3> This retrospective cohort study includes lung, esophageal, pancreatic, rectal and head and neck cancer patients throughout the US insured by a large health plan from 1/1/18 to 12/31/21. We defined total same-day visit costs (TVC) as all radiation costs incurred in the visit, total RT cost of care (TRC) as the total RT costs incurred between the first and last RT visit and total cost of care (TCC) as the total cost of care for all medical and pharmacy benefits incurred between the first and last RT visit. Costs were compared by SOC (outpatient-office (OO) vs. outpatient-hospital (OH)). We used a t-test for univariate analysis and multivariate linear regression to predict the continuous outcomes of TVC, TRC and TCC. We evaluated the performance of the TVC regression overall and by local market to assess regional cost differences where p<0.05 and R²>0.50 were deemed significant. <h3>Results</h3> We evaluated 16,818 patients in our study. In unadjusted analyses, treatments rendered in the OH cost significantly more than those rendered in the OO. We observed an extremely weak correlation between the distance from home-to-SOC for TVC (r=0.031), TRC (r=0.031) and TCC (r = 0.036). In multivariate regression models, treatments in the OH setting cost more than those rendered in the OO setting by $295.18 (TVC, 61.6% more), $5,857.64 (TRC, 57.1% more) and $7,882.93 (TCC, 31.6% more). Variables highly predictive of cost increases in TVC, TRC and TCC include receiving care in an OH setting, being commercial fully insured, median income (measured as US Census reported ZIP CODE median), chemotherapy and hydration. Malnutrition (defined as having a malnutrition diagnosis in the last 30 days) had a significant impact on costs in all models; in the TVC and TRC models, it reduced costs whereas in the TCC model it increased costs. Likewise, palliative care had a significant impact on all models; in the TVC model, it increased costs. In the TRC and TCC models, it reduced costs. The local market analysis of the TVC model identified unusual cost variation between OO and OH visits not observed in the overall model with maximum variations in the local market ranging from -$0.5k to $20k from the original model's coefficient. In addition, the TVC model shows the home-to-index SOC coefficient as $0.07/mile but larger variation at the local level up to $44,230/mile. <h3>Conclusion</h3> In this study, radiotherapy costs are highly variable based on local markets. OH treatment setting, being commercial fully insured, median income, chemotherapy and hydration predicted higher costs. Home-to-index SOC distance is not operationally impactful at the national level but is important in select regional communities. Further investigation is needed to define this variability and to define opportunities for standardizing the cost of radiotherapy delivery while improving access and quality of care.

Abstract 6172: Artificial intelligence-powered spatial analysis of tumor-infiltrating lymphocytes reveals immune-excluded phenotype is correlated with TGF-beta pathway related genomic aberrations

Abstract Aberrant transforming growth factor-beta(TGF-B) pathway in the tumor microenvironment has been highlighted as one of the core resistance pathways of immunotherapy, by excluding tumor-infiltrating lymphocytes (TIL) out of the tumor area. However, no studies have coupled immune phenotypes classified by spatial analysis of TIL in whole slide images (WSI) with TGF-B pathway analysis on a large-scale database. Here, we hypothesized that the immune-excluded phenotype classified by a deep-learning spatial analysis model, Lunit SCOPE IO, would be correlated with the aberrant TGF-B pathway in The Cancer Genome Atlas (TCGA) cohorts. Aberrant TGF-B pathway was measured by Trimmed Mean of M-values (TMM) normalized and transformed to log2 of counts-per-million of previously published gene sets of fibroblast-specific TGF-beta responsive gene signature, using edgeR packages from TCGA RNA-sequencing data (n=6,709) across the 23 cancer types. Lunit SCOPE IO was developed to identify immune phenotypes trained and validated from 3,166 multi-cancer H&amp;E WSI with sections of 2.8e+9 mm2 tumor tissue containing 5.9e+6 TIL annotated by 52 board-certified pathologists. Lunit SCOPE IO classified immune phenotypes as immune-inflamed and -excluded according to the proportion of TIL density either highly conserved in cancer epithelium (CE) or cancer stroma (CS), respectively, and otherwise, classified as immune-desert with low TIL density in CE and CS. Aberrant TGF-B expression was highly enriched in multiple cancer types including pancreatic cancer, head and neck cancer, kidney clear cell carcinoma, lung squamous cell carcinoma, and breast cancer, in ascending order. TGF-B expression was increased in microsatellite-stable tumor samples (p = 7.4e-15) or samples with low tumor mutational burden (TMB, &amp;lt; 10/megabase, p = 4.9e-8), compared to those with microsatellite instability-high or high TMB, respectively. Interestingly, TGF-B expression was highly correlated with the proportion of cancer stroma in WSI (R = 0.315, p &amp;lt; 2.2e-16) and the proportion of immune-excluded phenotype (R = 0.115, p &amp;lt; 2.2e-16) across multiple cancer types. Tumor samples with SMAD4 mutations (n = 161, 2.4%) had significantly higher TGF-B expression (p = 0.0190), and a higher proportion of immune-excluded phenotype (p &amp;lt; 2.2e-16) in WSI, compared to wild-type SMAD4. Aberrant TGF-B pathway is clearly associated with increased proportion of cancer stroma, and excluded TIL, or immune-excluded phenotype in a large-scale pan-carcinoma analysis. Citation Format: Gahee Park, Sanghoon Song, Hyung-Gyo Cho, Soo Ick Cho, Wonkyung Jung, Lunit AI team, Sergio Pereira, Donggeun Yoo, Kyunghyun Paeng, Chan-Young Ock. Artificial intelligence-powered spatial analysis of tumor-infiltrating lymphocytes reveals immune-excluded phenotype is correlated with TGF-beta pathway related genomic aberrations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6172.

Long-term effects of total vs. partial pancreatectomy among patients with pancreatic cancer: a population-based study.

BackgroundTotal pancreatectomy (TP) for pancreatic cancer (PC) has been limited historically for fear of elevated perioperative morbidity and mortality. With advances in perioperative care, TP may be an alternative option to partial pancreatectomy (PP). Limited evidence clarified the indication for these two procedures in PC patients, especially in patients with different tumor staging and location. Thus, this study aims to compare the outcomes after TP and PP for PCs of different T stages and locations.MethodsThe study identified 14,456 PC patients with potentially curable primary tumor (T1–3) who received TP or PP from the Surveillance, Epidemiology, and End Results (SEER) database during 2000 to 2016. Detailed clinical and tumor covariates were all collected. Overall survival (OS) and cancer-specific survival (CSS) were the primary endpoints of interest in this study. OS and CSS were compared between patients after TP and PP using log-rank analysis.ResultsFor all patients, except for tumor location, TP group was comparable to the PP group. OS and CSS of the TP group were worse than of the PP group (median OS: 19 vs. 20 months, P=0.0058; median CSS: 24 vs. 26 months, P=0.00098, respectively). In stratifying analyses, TP was significantly related to worse OS and CSS than PP in pancreatic head and neck cancer patients with T2-stage tumors (median OS: 18 vs. 19 months, P=0.0016; median CSS: 22 vs. 24 months, P=0.00055, respectively), whereas for patients with T1- or T3-stage pancreatic head and neck cancer as well as T1- to T3-stage pancreatic body and tail cancer or overlapping location cancer, OS and CSS of the two groups were similar (all P>0.05).ConclusionsCompared with PP, TP offered worse prognosis in pancreatic head and neck cancer patients with T2-stage tumors, furthermore, TP and PP achieved comparable prognosis in patients with T1- or T3-stage pancreatic head and neck cancer as well as T1- to T3-stage pancreatic body and tail cancer or overlapping location cancer.

Cross-link between ferroptosis and nasopharyngeal carcinoma: New approach to radiotherapy sensitization.

Ferroptosis is a recently discovered special type of regulated cell death that is strongly associated with both homeostasis maintenance and cancer development. Previous studies have indicated that a number of small-molecular agents inducing ferroptosis have great potential in the treatment of different types of cancer, including breast, pancreatic, prostate and head and neck cancer. However, the role of ferroptosis in nasopharyngeal carcinoma (NPC) has remained to be fully determined. To the best of our knowledge, no review of the currently available studies on this subject has been published to date. The metabolism and expression of specific genes that regulate ferroptosis may represent a promising radiosensitization target in cancer treatment. The aim of the present review was to describe the cross-link between ferroptosis and NPC and to discuss the potential value of regulators and the possible mechanism underlying the role of ferroptosis in the radiosensitization of NPC, in the hope that linking the mechanism of ferroptosis with the development of NPC will accelerate the development of novel ferroptosis-based targets and radiotherapy strategies in NPC.

Abstract C021: Characteristics of malignancy in lesbian, gay, bisexual, and transgender/transsexual (LGBT) population

Abstract Background: LGBT people account for 4.5% of adult population in U.S. and face multiple challenges across different aspects of life. Although malignancy is the second most common cause of death in the U.S., only few studies that analyzed the characteristics of malignancies in the LGBT community exist. We aim to provide an overview of malignancy affecting LGBT patients. Methods: A retrospective chart review of LGBT patients with a diagnosis of malignancy treated at Medstar Health Hospitals was performed. Natural language processing with strings was utilized to retrieve patient charts with ICD-9 and ICD-10 codes for LGBT status and cancer. Results: A total of sixty-one patients (pts) were identified; (5 lesbian female, 49 gay male, 6 female transgenders and 1 male transgender). The median age was 49 (range: 19-79). 30 pts (49%) were Caucasian, 26 (43%) were African American and 5 (8%) were Hispanic. Among the female transgender patients, 3 received hormonal therapy for gender change and no patient underwent surgery to change the biological gender. 18 pts had human immunodeficiency virus (HIV) infection, 1 pt hepatitis B virus (HBV), 2 pts hepatitis C virus (HCV), 8 pts HIV/HCV, 2 pts HIV/HBV, and 1 pt HIV/HBV/HCV. Among the patients with HIV infection (n=29), 26 (90%) were receiving anti-retroviral treatment at last follow-up. 27 (44%) pts were active smokers, 10 (16%) pts former smokers and 24 (40%) never smoker. 27 (44%) reported a history of substance abuse with 9 (15%) pts with active substance abuse and 25 (41%) never used it. Employment status was employed (n=32), unemployed (n=20), retired (n=6), and not available (n=3). Tumor types included anal squamous cell carcinoma (anal SCC; n=15), Non-Hodgkin lymphoma (NHL; n=12), non-small-cell lung cancer (NSCLC; n=9), colorectal cancer (CRC; n=7), Kaposi sarcoma (n=4), brain cancer (n=3), breast carcinoma, small-cell lung cancer and pancreatic cancer (2 each), prostate carcinoma, testicular carcinoma, head and neck cancer, Hodgkin lymphoma and mesothelioma (1 each). Among the HIV-infected patients, tumor types include [NHL n=8, anal SCC n=6, NSCLC n=4, CRC n=4, Kaposi sarcoma n=3, head and neck cancer =1, prostate cancer n=1, pancreatic cancer n=1, Hodgkin lymphoma n=1]. Among the anal SCC group (n=15), 6 pts had human papilloma (HPV)-associated cancer, while 1 pt had non-HPV associated cancer and HPV status was not available in 8 pts. Conclusion: LGBT people with cancer have a high incidence of chronic viral infection and appear to have distinct patterns of malignancy compared to those in the general population. Larger studies are needed to verify the findings and to understand unique challenges facing the LGBT population. Citation Format: Ghassan Al-Shbool, Saira Farid, Ahmad Nassar, Chul Kim. Characteristics of malignancy in lesbian, gay, bisexual, and transgender/transsexual (LGBT) population [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr C021.

2019 ASCO Annual Meeting Highlights for the Advanced Practitioner: Other Solid Cancers.

Trials studying additional solid cancers, such as pancreatic cancer, head and neck cancer, glioblastoma, and glioma are reviewed in this section and accompanied by advanced practitioner commentaries. In addition, a study exploring the benefits of proton therapy over photon therapy is discussed.

Black Patients Experience Highest Rates of Specific Cancer-Associated Venous Thromboembolism: A Study Based at a Large Safety-Net Hospital in New England

Background: Several studies have shown that cancer is associated with a 2 to 9-fold increased risk of venous thromboembolism (VTE) (Heit 2000; Hutton 2000; Hansson 2000; Prandoni 2002; Descourt 2006), with an absolute risk ranging from 1%-8% (Timp 2013). Importantly, the presence of VTE significantly reduces the 1-year survival rate from 36% in cancer patients without VTE to 12% in cancer patients with VTE (Sorensen 2000). Large cohort studies in the general population have suggested that Blacks compared to Whites are at higher risk of developing VTE (Zakai 2014). However, studies examining the influence of race on specific cancer-associated VTE have been scarce. To address racial disparities in cancer-associated VTE, we conducted a retrospective study in the largest safety-net hospital in New England, Boston Medical Center, with a large cancer cohort consisting of a substantial number of Black patients. This has provided a unique opportunity to directly compare the risk of specific cancer-associated VTE between Black and White cancer patients which could lead to future mechanisms-based studies.Methods: Summary statistics were performed and presented as mean, proportion and their respective standard deviation. Differences between blacks and whites for various variables were tested using Student's t-test, Pearson's Chi-square, and Fisher's exact test as appropriate using RStudio software (v1.0.153). Logistic regression was then used to estimate and compare odds of VTE occurrence in Lung cancer after adjusting for other confounders. Statistical significance was assessed at p <0.05.Results: We analyzed 16,498 cases with all types of solid organ and hematologic malignancies from 2004 to present (2018) with case mix characterized by Whites (53%) and Blacks (33%) and Others (11.7%). Our review of the electronic medical record revealed that 238 (1.4%) of 16,498 cancer patients had VTE, either at presentation or within one year following the cancer diagnosis. Since some VTE cases might have been undiagnosed prior to cancer development/manifestation, we used the term cancer-associated VTE to denote co-existence of these pathologies. The proportion of VTE cases were similar among male (55.5%) and female patients (44.1%). Of 238 cases of cancer presenting with VTE, Blacks predominated with 121 cases (51.3%) compared to 65 cases of Whites (27.5%). Interestingly, selected cancers were more associated with VTE in Blacks. As shown in Table 1, a significantly higher proportion of cancer-associated VTE was observed in Black patients with lung cancer, >breast cancer, >prostate cancer, >colorectal cancer and gastric/small bowel cancer; in descending order. VTE occurrence was observed predominantly in the pulmonary artery (36.9%) and femoral/iliac vein (16.1%). Sixteen percent of patients with cancer-associated VTE experienced recurrent VTE, however, no statistical difference in race was seen (p= 0.6). Given the high number of cases of lung cancer with VTE, we examined the influence of race with adjustment for confounders. Our logistic regression model showed that Black lung cancer patients have a significantly higher odds of developing cancer-associated VTE even after adjusting for cancer stage, age, and sex (OR- 2.39, CI = 1.26-4.60, p = 0.0079). Interestingly, the proportions of VTE in cancers such as pancreatic cancer, head and neck cancer and glioblastoma, were equally observed in Black and White patients, which can be ascribed to low event rates of VTE in these cancers in this series.Conclusions: This single-center study suggests that a higher proportion of Black cancer patients exhibited cancer-associated VTE compared to White cancer patients. Importantly, this significant difference was especially reflected in specific cancer subtypes. Race had an independent effect on cancer-associated VTE but showed no significant influence on recurrent VTE. Our current investigation motivates additional large-scale studies of cohorts with substantial representation of Blacks and ethnic minorities to further identify factors that contribute to racial disparities in the context of cancer-associated VTE, thus guiding necessary interventions to maximize outcome. Our study also lays the ground for mechanistic cause-and-effect inquiries related to intricate associations of specific cancers with VTE in a certain races. DisclosuresBrophy:Novartis: Research Funding.

Genetic Alterations of TRAF Proteins in Human Cancers.

The tumor necrosis factor receptor (TNF-R)-associated factor (TRAF) family of cytoplasmic adaptor proteins regulate the signal transduction pathways of a variety of receptors, including the TNF-R superfamily, Toll-like receptors (TLRs), NOD-like receptors (NLRs), RIG-I-like receptors (RLRs), and cytokine receptors. TRAF-dependent signaling pathways participate in a diverse array of important cellular processes, including the survival, proliferation, differentiation, and activation of different cell types. Many of these TRAF-dependent signaling pathways have been implicated in cancer pathogenesis. Here we analyze the current evidence of genetic alterations of TRAF molecules available from The Cancer Genome Atlas (TCGA) and the Catalog of Somatic Mutations in Cancer (COSMIC) as well as the published literature, including copy number variations and mutation landscape of TRAFs in various human cancers. Such analyses reveal that both gain- and loss-of-function genetic alterations of different TRAF proteins are commonly present in a number of human cancers. These include pancreatic cancer, meningioma, breast cancer, prostate cancer, lung cancer, liver cancer, head and neck cancer, stomach cancer, colon cancer, bladder cancer, uterine cancer, melanoma, sarcoma, and B cell malignancies, among others. Furthermore, we summarize the key in vivo and in vitro evidence that demonstrates the causal roles of genetic alterations of TRAF proteins in tumorigenesis within different cell types and organs. Taken together, the information presented in this review provides a rationale for the development of therapeutic strategies to manipulate TRAF proteins or TRAF-dependent signaling pathways in different human cancers by precision medicine.

A Novel Classification and Staged Approach for Dissection Along the Celiac and Hepatic Artery During Pancreaticoduodenectomy

In recent decades, there have been enthusiastic discussions of, and active proposals for, new approaches to dissection around the superior mesenteric artery during pancreaticoduodenectomy (PD). In contrast, dissection along the celiac axis (CA) and hepatic artery (HA) and in the hepatoduodenal ligament has rarely been systematically discussed. In this report, we propose and describe a three-level classification of dissection along the CA-HA system which is applicable to a variety of diseases for which PD is indicated. The extent of dissection is classified into three levels. With the first level (LV-1), neither LN nor plexus dissection is required. The second level (LV-2) includes en bloc resection of LNs along the CA, HA, and in the hepatoduodenal ligament, preserving the nerve plexus around the artery. The third level (LV-3) includes en bloc dissection of LNs and the nerve plexus close to cancer invasion, for example, being accompanied by half circumferential dissection of the nerve plexus around the CA or circumferential dissection of that of HA. LV-1 dissection is indicated for benign lesions, low grade malignancy, pancreatic metastasis, or intraductal papillary mucinous neoplasm. LV-2 is indicated for periampullary malignancies requiring dissection of regional LNs, including ampullary, distal bile duct, duodenal cancers, and pancreatic cancers without evidence of invasion around the CA-HA system. LV-3 is indicated for malignancies with evidence of perineural invasion in the CA-HA system, such as pancreatic cancer at the pancreatic neck or advanced bile duct cancer. In combination with classified superior mesenteric artery dissection, a variety of PD procedures would be systematically classified, understood, and reproduced regardless of nature of disease, surgeon, or approach.

The presence of glutamate residues on the PAS sequence of the stimuli-sensitive nano-ferritin improves in vivo biodistribution and mitoxantrone encapsulation homogeneity

A genetically engineered human ferritin heavy chain (HFt)-based construct has been recently shown by our group to efficiently entrap and deliver doxorubicin to cancer cells. This construct, named HFt-MP-PAS, contained a tumor-selective sequence (MP) responsive to proteolytic cleavage by tumor proteases (MMPs), located between each HFt subunit and an outer shielding polypeptide sequence rich in proline (P), serine (S) and alanine (A) residues (PAS). HFt-MP-PAS displayed excellent therapeutic efficacy in xenogenic pancreatic and head and neck cancer models in vivo, leading to a significant increase in overall animal survivals. Here we report a new construct obtained by the genetic insertion of two glutamate residues in the PAS sequence of HFt-MP-PAS. Such new construct, named HFt-MP-PASE, is characterized by improved performances as drug biodistribution in a xenogenic pancreatic cancer model in vivo.Moreover, HFt-MP-PASE efficiently encapsulates the anti-cancer drug mitoxantrone (MIT), and the resulting MIT-loaded nanoparticles proved to be more soluble and monodispersed than the HFt-MP-PAS counterparts. Importantly, in vitro MIT-loaded HFt-MP-PASE kills several cancer cell lines of different origin (colon, breast, sarcoma and pancreas) at least as efficiently as the free drug. Finally, our MIT loaded protein nanocages allowed in vivo an impressive incrementing of the drug accumulation in the tumor with respect to the free drug.

Abstract 5467: Phosphoproteomic analysis of pyruvate dehydrogenase in response to environmental stress

Abstract Pyruvate dehydrogenase is a mitochondrial enzyme that regulates the flux of carbohydrates into oxidative phosphorylation. The activity of PDH is largely regulated by reversible phosphorylation. The pyruvate dehydrogenase kinases add inhibitory phosphorylations to PDH on the E1α subunit at positions 232, 293, and 300. Interestingly, there is a family of 4 related PDHK genes with overlapping affinity for the 3 phosphorylation sites. PDHK1 and PDHK3 have been identified as hypoxia-inducible at the transcriptional level, and PDHK1 has been shown to be important for the growth of model tumors. This work attempts to more carefully define the functions of PDHK1 and 3 using CRISPR technology in colorectal cancer lines in vitro and genetically engineered mice in vivo. Using antibodies specific for the phosphorylated sites on E1α, we find that PDHK1 is essential for the phosphorylation of the 232 site in response to hypoxia and partially responsible for the hyperphosphorylation of 293 and 300. The level of phosphorylation in response to hypoxia is also sensitive to nutrients in the environment, with high levels of glucose enhancing E1α phosphorylation in hypoxia. Analysis of the number of phosporylations on individual E1α molecules using isoelectric focusing shows a range of events, with some molecules having 2 or 3 phosphorylations, while a large fraction of the E1α remains unphosphorylated in hypoxia. This type of pattern suggests a non-random phosphorylation of the multiple sites. Analysis of PDH activity supports the in vitro findings that any single phosphorylation event is sufficient to inhibit PDH complex activity. Preliminary mitochondrial oxygen consumption experiments show that colorectal cancer cells are less dependent on PDHK1 for regulating mitochondrial function compared to published data in pancreatic and head and neck cancer. Finally, analysis of PDH phosphorylation in mice supports a role for PDHK1 in the regulation of PDH activity in response to fasting and blood glucose levels. In conclusion, regulation of PDH in normal and cancerous colonocytes appears to be sensitive to environmental oxygen and nutrients. PDHK1 is the PDHK family member with the greatest influence on the addition of non-random inhibitory phosphorylation events. These in vitro findings will be analyzed with respect to the findings obtained using the new PDHK1 fl/fl villin Cre mouse. Citation Format: Wendi O'Neill, Tereza Golias, Martin Benej, Nicholas Denko. Phosphoproteomic analysis of pyruvate dehydrogenase in response to environmental stress [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5467. doi:10.1158/1538-7445.AM2017-5467

Lymphopenia association with planning target volume and lung V5 and its effect on survival of esophageal cancer receiving neoadjuvant chemo-radiation with Dutch CROSS regime

Introduction: Radiation has a strong lympholytic effect. This effect has been overlooked for decades until recently. As immunotherapy is becoming one of the main systemic treatment of various cancer, it is important to adopt best radiation technique to preserve lymphocyte numbers. Radiation-induced lymphopenia has been reported to be adversely associated with overall survival and recurrence free survival in various cancers including lung, pancreatic and head and neck cancer. Data of lymphopenia effect on esophageal cancer is lacking. We therefore sought to study the association of lymphopenia and overall survival in esophageal cancer patients who have undergone neoadjuvant chemo-radiation according to Dutch CROSS trial regime. One of the possible mechanism of severe lymphopenia in radiotherapy is the large volume of low dose bath killing large number of circulating lymphocytes in both systemic and pulmonary circulation. As there is report of relationship of low dose lung dosimetry parameters with lymphopenia in NSCLC, we also aim to study this relationship in esophageal cancer. Methods: All esophageal cancer patients from June 2012 to April 2015 in our tertiary university hospital who have received neoadjuvant chemo-radiation according to Dutch CROSS trial regime has been retrospectively reviewed. Total subjects eligible for review is 51. One subject has died before the start of chemo-radiation and thus was excluded from analysis. Lymphocyte nadir was defined as the minimum lymphocyte value measured between the start of neoadjuvant chemo-radiation and the operation date. Relationships between lymphocyte nadirs with overall survival (OS) and recurrence free survival (RFS) were evaluated with Cox-regression analysis. Association between Planning Target volume (PTV) and lung dose- volume histogram (DVH) parameters were analysed with Pearson correlation coefficients. Results: 48 out of 50 subjects have normal baseline lymphocyte counts. Low lymphocyte nadir is found to have negative effect on patient's overall survival (OS). On multi-variable Cox regression with backward elimination analysis, patients with higher lymphocyte nadirs exhibited significantly improved OS (hazard ratio [HR] Z = 0.656 per 0.1 x 10^9 lymphocytes/L, p = 0.009). Of note, no significant relationships with OS were seen in baseline total white cell count, lymphocyte count and neutrophil count. Analyses of lung DVH parameters revealed significant correlations at lower doses (lung V1-V15: P < 0.001). The absolute value Pearson correlation coefficient incrementally decreased and became nonsignificant at higher doses (lung V25: P>.05). For instance, the correlation coefficient of V1, V5 and V10 were -0.566, -0.495 and -0.419 respectively. Larger PTV was also associated with lower lymphocyte nadir (r= -0.367 P = 0.008). Conclusion: Lower lymphocyte nadir is associated with poorer overall survival in this group of patients. Higher low dose lung DVH and larger PTV are associated with lower lymphocyte nadir. These findings shall be confirmed with prospective data in future studies. This also suggests immune preserving radiation strategy in radiation by suppressing low dose lung DVH may improve OS in this group of patients.

The characteristics of pancreatic neck cancer.

337 Background: Pancreatic neck cancer occurs in the small region surrounded by the common hepatic artery (CHA), gastroduodenal artery (GDA), and portal vein (PV). The specific clinicopathological characteristics of pancreatic neck cancer remain unclear. This study aimed to identify specific biological behaviors of pancreatic neck cancer for the improvement of treatment outcomes. Methods: This study was a retrospective cohort study and comparative outcomes design. In 63 (19.4%) of 325 consecutive pancreatic cancer patients who underwent surgery, the tumor was located in the pancreatic neck. Clinicopathological characteristics and prognostic factors specific to pancreatic neck cancer were analyzed by comparison to those of pancreatic head or body/tail cancers. Results: The rates of radiographic and pathological PV and/or superior mesenteric vein (PV/SMV) invasion were higher in patients with pancreatic neck cancer (radiographic: 84.1%, pathological: 36.5%) than those with pancreatic head and body/tail cancers (radiographic, head: 67.3%, body/tail: 25.0%, pathological, head: 26.0%, body/tail: 6.3%). The most frequent lymph node metastasis was found in the region along the CHA in pancreatic neck cancer, and the spots most likely to show a positive surgical margin were the dissected surface of the PV and the root of the GDA and/or CHA. For pancreatic neck cancer patients, five independent poor prognostic factors were found: pathological PV/SMV invasion (P= 0.005), moderately or poorly differentiation (P= 0.001), positive lymph node ratio ≥ 0.1 (P&lt; 0.001), surgical margin length ≤ 1 mm (P= 0.018), and no completion of planned postoperative adjuvant therapy (P&lt; 0.001). Conclusions: Pancreatic neck cancer showed specific clinicopathological characteristics and prognostic factors after resection. Patients with these risk factors might need multimodality treatment strategies, including neoadjuvant therapy, in order to prolong the survival, although further studies will be necessary to confirm our findings.

Pancreatic neck cancer has specific and oncologic characteristics regarding portal vein invasion and lymph node metastasis

Pancreatic cancer originating in the neck of the gland occurs in the small region surrounded by the common hepatic artery (CHA), gastroduodenal artery (GDA), and portal vein (PV). The specific clinicopathologic characteristics of pancreatic neck cancer remain unclear. Our aim was to identify specific biologic behaviors of pancreatic neck cancer for the improvement of treatment outcomes. This study was a retrospective cohort study with a comparative outcomes design. In 63 of 325 consecutive patients (19.4%) with pancreatic cancer who underwent operation, the tumor was located in the pancreatic neck. Clinicopathologic characteristics and prognostic factors specific to pancreatic neck cancer were analyzed by comparison with those of pancreatic head or body/tail cancers. The rates of radiographic and pathologic PV and/or superior mesenteric vein (PV/SMV) invasion were greater in patients with pancreatic neck cancer (radiographic, 84%; pathologic, 37%) than those with pancreatic head and body/tail cancers (radiographic: 67% head, 25% body/tail; pathologic: 26% head, 6% body/tail). The most frequent lymph node (LN) metastases were found in the region along the CHA in pancreatic neck cancer, and the areas most likely to show a positive surgical margin were the dissected surface of the PV and the root of the GDA and/or CHA. For pancreatic neck cancer patients, 5 independent poor prognostic factors were found: pathologic PV/SMV invasion (P=.005), moderately or poorly differentiated tumors (P=.001), positive LN ratio of ≥0.1 (P<.001), distance from surgical margin of ≤1mm(P=.018), and inability to complete the planned postoperative adjuvant therapy (P<.001). Pancreatic neck cancer showed specific clinicopathologic characteristics and prognostic factors after resection.