Hepatic Progression Research Articles

Antitumor efficacy of concurrent everolimus with hepatic transarterial bland embolization (evero-embo) in patients with metastatic well differentiated neuroendocrine tumor (NET).

4115 Background: Hepatic transarterial embolization (HAE) is an effective loco-regional therapy for neuroendocrine tumor (NET) management. Systemic targeted therapies, such as everolimus and sunitinib, are typically held 2-4 weeks prior to and after procedures. The safety of concurrent use of everolimus with HAE has been previously reported (GI-ASCO). HAE induces anoxic injury while everolimus effects cell growth, proliferation and survival. Combining these two modalities may result in clinical synthetic lethality effectively debulking significant hepatic disease and/or delay progression. Historically bland HAE has a median hepatic PFS of ~9 months. In this study, the clinical efficacy of evero-embo is examined. Methods: A review of clinical and radiographic data was conducted for all sequential patients who underwent evero-embo between September 2016 and April 2018 at the University of Kentucky Markey Cancer Center. An independent radiologist performed RECIST measurements. Patients were required to have had systemic everolimus for ≥ 1 month prior to embolization in order to be included in this study and be on everolimus immediately post procedure. Patients with at least 12 months post procedure follow up were included for efficacy review. Results: A total of 51 HAEs with concurrent systemic everolimus were performed in 34 NET patients. Twenty one of 24 patients were noted to have a partial response. Rest had stable disease. Hepatic progression was not observed. Twenty-one of the 34 patients have had 12 or more months of follow up post procedure (median of 17 months). None of these 21 patients have had hepatic progression. Conclusions: Evero-embo results in a partial response rate of 62% and may have significant antitumor activity when compared to bland hepatic artery embolization in NET patients. With a median follow-up of 17 mos, hepatic progression has not occurred in any patient. Additional follow up is necessary to compare the median hepatic PFS of evero-embo to the historical drug-eluting bead HAE PFS.

Intra-arterial Mitomycin C infusion in a large cohort of advanced liver metastatic breast cancer patients: safety, efficacy and factors influencing survival.

The aim of this study was to determine the safety and efficacy of Mitomycin C (MMC) infusion in a large cohort of advanced liver metastatic breast cancer patients (LMBC) and to determine factors influencing overall survival (OS). We retrospectively analysed LMBC patients, treated with MMC infusion between 2000 and 2017. Hepatic response was measured with baseline CT scans and first available CT scan after MMC infusion by RECIST 1.1 criteria. Adverse events were registered by the CTCAE version 5.0. OS and hepatic progression free survival (hPFS) were evaluated using Kaplan-Meier estimates. After univariable analysis, a stepwise forward multivariable (MV) prediction analysis was developed to select independent pre-treatment factors associated with OS. We included 176 patients with a total of 599 MMC infusions, mostly heavily pre-treated patients with a median time from diagnosis of MBC to MMC infusion of 36.9months. RECIST evaluation of liver lesions (n = 132) showed a partial response rate of 15%, stable disease of 43% and progressive disease in 17%. Adverse events grade 3 and 4 were reported in 17.5%. Median PFS was 5.5months and median OS was 7.8months. Significant independent baseline predictors of worse OS included number of prior systemic chemotherapy lines, prior liver ablation, higher liver tumour burden and elevated levels of bilirubin and ALT. MMC infusion is safe and effective in advanced LMBC patients. An increased number of prior therapies, a higher liver tumour burden and elevated levels of bilirubin and ALT were associated with a worse OS.

811 – Risk of Hepatic Disease Progression in Patients with Nonalcoholic Fatty Liver (NAFLD)-Related Cirrhosis

811 – Risk of Hepatic Disease Progression in Patients with Nonalcoholic Fatty Liver (NAFLD)-Related Cirrhosis

External beam radiotherapy for hepatocellular carcinoma with right atrium tumor thrombus.

328 Background: Hepatocellular carcinoma (HCC) with right atrium tumor thrombus (RATT) via progression through hepatic veins into the inferior venal cava is a challenging entity with limited treatment options. Given the significant clinical sequelae of RATT, improved locoregional treatments are needed. We examined our experience with palliative right atrium-directed radiotherapy for HCC RATT. Methods: We conducted a retrospective study of 10 patients with HCC RATT treated with radiotherapy between 2011-2018. Patients with localized (n = 5) and metastatic (n = 5) disease were included. Clinical and treatment factors were collected. Results: Median follow-up was 3 mos. Baseline Childs Pugh score was A in 3 patients and B in 7 patients. The table below shows prescription and dosimetric data. No patients experienced grade ≥ 3 toxicity. The only major adverse cardiac event observed after radiotherapy was heart failure in 2 patients, and it was difficult to determine the contribution of treatment versus RATT. Three months post-radiation, 2 patients experienced a Childs Pugh score decline of > 2 points. At last follow-up, 5 patients were deceased, 4 patients were alive without progression, and 1 patient was alive with progression. Median progression free and overall survival was 3 mos (0.5-7 mos) and 3.5 mos (range 0.5-13 mos), respectively. RATT progression occurred in 1 patient, hepatic progression outside the treatment field occurred in 1 patient, and distant progression occurred in 2 patients. Causes of death included RATT progression (n = 1), HCC progression elsewhere (n = 2), hepatic decompensation (n = 1), and aspiration (n = 1). Conclusions: This unique series suggests HCC RATT-directed radiotherapy may be safe and locally effective. Prospective study is needed to understand the optimal treatment of these patients. [Table: see text]

ALPPS procedure in an experimental colorectal liver metastases model: hero or villain?

Background: Associated liver partition and portal vein ligation for staged hepatectomy (ALPPS) has been raised as a potential therapy for bilobar metastatic liver disease, although the potential tumor progression (TP) that this technique may induce is still not well established. Methods: The aim of this report was to study tumor hepatic progression induced by the first step of ALPPS in a WAG/Rij rat syngenic model of metastatic colorectal carcinoma by subcapsular inoculation of CC531 cell line. We analyzed the effect of hypoxia and immune response induced by ALPPS on liver metastases. Results: ALLPS seems to induce not only tumor progression, but also metastases independently of the site of inoculation. Immunohistochemical analisys revealed that ALPPS induced expression of hepatic vasculogenic factors and a dramatic increase of intrahepatic macrophages in comparison with non-operated groups. Interestingly, hepatic macrophages strongly expressed COX-2, while tumor-infiltrating macrophages expressed mainly arginase-1. ALPPS also induced a decrease of tumor-infiltrating lymphocytes and increase of intrahepatic T-lymphocytes. Conclusion: ALPPS technique may induce hypoxic environment which enhance hepatic HIF1alpha and VEGF expression. Additionally, the regenerative stimulus seems to be driven by a pro-inflammatory environment, in which M1 intrahepatic macrophages, which expressed COX-2 may develop a key role. These facts may be related with the tumor progression observed in inoculated and operated animals.

Fatores Prognósticos Associados à Eficácia da Embolização Transarterial Hepática em Pacientes com Tumores Neuroendócrinos

INTRODUCTION: To evaluate the safety and e?cacy of hepatic transarterial embolization (TAE) or transarterial chemoembolization (TACE) in patients with irresectable liver metastases from neuroendocrine tumors (NETs) treated at two Brazilian cancer centers. METHODS: Retrospective multicenter analysis of patients (pts) with histological diagnosis of neuroendocrine tumor of any origin with unresectable and measurable hepatic metastases who underwent at least one procedure of TAE or TACE. ENDPOINTS: Hepatic progression free survival (HPFS), overall survival (OS), tumor response and toxicity assessment. RESULTS: Thirty-six pts were evaluated. Primary tumors were as follow: midgut 20 pts, pancreas 7 pts, others 9 pts. Most of patients had grade (G) 1-2 tumors (93.3%). In patients with functioning NETs, clinically signi?cant symptomatic control was 41.7%. Concerning type of embolization (TAE vs TACE), there were no signi?cant di?erences in the proportion of patients achieving reduction of at least 50% of 5HIAA (45.5% vs 50%) and radiological disease control rate (91.3% vs 92.3%), respectively. In a median follow up of 40.8 months (m), median HPFS was 38.9m, and mean OS was 98m (median not reached). No signi?cant di?erences were found in HPFS or OS by type of embolization procedure. Pancreatic primary tumor and G3 tumor by WHO classi?cation were associated with signi?cantly shorter HPFS. Tumor G3 was also associated with shorter OS. Adverse events of any grade were: abdominal pain (13.8%), fever (5.5%), and 2 pts developed biloma. CONCLUSION: Our study is the ?rst in our region reporting results of TAE/TACE in patients with irresectable liver metastases from NETs. We observed that pts with pancreatic or G3 NET derive less bene?t from these procedures. In pts with G1-2 NETs, both techniques oer similar results.

English

Hepatitis B infection (HBV) infection is a serious public health problem worldwide and its co-infection with human immune deficiency virus (HIV) is common due to shared routes of transmission. An increased mortality due to accelerated hepatic disease progression and the frequent hepatotoxicity caused by antiretroviral therapy are the challenges in the clinical management of HIV. Epidemiological studies on HBV and HBV/HIV co infection are scarce in Ethiopia, particularly at the study area. The aim of this study was to determine the magnitude of HBV, its risk factors and co-infection with HIV among clients of a voluntary counseling and testing (VCT) center in Southern Ethiopia. A facility based cross-sectional study was conducted from 1st February 2016 to 15th March among clients of Nigist Eleni Memorial Hospital VCT Center. Data were collected by face-to-face interview and specific formula sheet as well recorded results of laboratory diagnosis of blood sample from each participant. Both descriptive and inferential statistics were used for data analysis. Multivariable logistic regression modeling was done to identify predictors of HBV. Overall, 331 participants were included in the study. The prevalence of HBV was 8.8%, HBV/HIV co-infection was found in 3.6%. Individuals with a history of multiple sexual partner [AOR = 10.3; 95% CI, 3.71 - 28.83], previous history of invasive procedure [adjusted odds ratio (AOR) = 10.88; 95% CI, 3.84 - 30.86] and history of surgical procedure [AOR = 9.2; 95% CI, 3.1 - 27.88] were identified as in dependent predictors of HBV infection. High HBV infection and HBV/HIV co-infection was found in the study. Previous history of surgical procedure, invasive procedure and multiple sexual partners were identified as independent predictor of HBV infection. Key words: Hepatitis B virus (HBV), human immune deficiency virus, HBV-HIV co-infection, risk factors, Hosanna.

DAXX Mutation Status of Embolization-Treated Neuroendocrine Tumors Predicts Shorter Time to Hepatic Progression

PurposeTo identify common gene mutations in patients with neuroendocrine liver metastases (NLM) undergoing transarterial embolization (TAE) and establish relationship between these mutations and response to TAE. Materials and MethodsPatients (n = 51; mean age 61 y; 29 men, 22 women) with NLMs who underwent TAE and had available mutation analysis were identified. Mutation status and clinical variables were recorded and evaluated in relation to hepatic progression-free survival (HPFS) (Cox proportional hazards) and time to hepatic progression (TTHP) (competing risk proportional hazards). Subgroup analysis of patients with pancreatic NLM was performed using Fisher exact test to identify correlation between mutation and event (hepatic progression or death) by 6 months. Changes in mutation status over time and across specimens in a subset of patients were recorded. ResultsTechnical success of TAE was 100%. Common mutations identified were MEN1 (16/51; 31%) and DAXX (13/51; 25%). Median overall survival was 48.7 months. DAXX mutation status (hazard ratio = 6.21; 95% confidence interval [CI], 2.67–14.48; P < .001) and tumor grade (hazard ratio = 3.05; 95% CI, 1.80–5.17; P < .001) were associated with shorter HPFS and TTHP on univariate and multivariate analysis. Median HPFS was 3.6 months (95% CI, 1.7–5.3) for patients with DAXX mutation compared with 8.9 months (95% CI, 6.6–11.4) for patients with DAXX wild-type status. In patients with pancreatic NLMs, DAXX mutation status was associated with hepatic progression or death by 6 months (P = .024). DAXX mutation status was concordant between primary and metastatic sites. ConclusionsDAXX mutation is common in patients with pancreatic NLMs. DAXX mutation status is associated with shorter HPFS and TTHP after TAE.

Prognostic role of neutrophil-to-lymphocyte ratio in unresectable hepatocellular cancer patients treated with trans-arterial chemoembolization

The neutrophil-to-lymphocyte ratio (NLR), a useful biomarker, reflects systemic inflammation responses which are closely associated with the prognosis of various malignancies. Nevertheless, the prognostic significance of NLR in patients with hepatocellular carcinoma (HCC) undergoing trans-arterial chemoembolization (TACE) remains controversial. The study was designed to determine the prognostic value of NLR in survival outcomes of HCC patients receiving TACE by systematical review of present literature. Medline, Embase, Web of Science and Cochrane library databases were searched according to a pre-specified inclusive strategy to identify studies concerning survival in HCC patients receiving TACE with high or low pre- or post-TACE NLR. An electronic Excel table was used to extract epidemiological information, clinical pathological characteristics as well as primary outcome data. Initially, 598 relevant articles were selected, of which, 13 articles including 1,648 unresectable HCC patients undergoing TACE were ultimately enrolled. Our review and meta-analysis demonstrated that a high pre-TACE NLR reflected unfavorable overall survival (OS) [pooled hazard ratio (HR): 1.53, pooled 95% confidence interval (CI): 1.29–1.78, P 0.05) and tumor response (P=0.088). A high post-TACE NLR was closely associated with metastasis (OR: 1.57, 95% CI: 0.732–3.382, P=0.246), but not with time to progression (TTP) (P=0.18) and tumor response (P=0.229), and controversial role with OS (P value: 0.001 vs . 0.342). The NLR change trend between pre-and post-TACE was not correlated with either tumor response to TACE (P=0.89) or hepatic progression (P=0.55), whereas its prognostic role with OS was also controversial (P>0.05 or <0.05). As a convenient, inexpensive and easily available inflammatory biomarker, NLR harbored its important value in prognostic prediction in patients with unresectable HCC undergoing TACE. However, the association of the changing trends of NLR and NLR at different stages with different prognostic endpoints in HCC patients undergoing TACE was still in controversy, therefore further large-scale, prospective studies are needed to confirm these findings.

Role of Kupffer cells in the progression of CRC liver metastases after the first stage of ALPPS

Associated liver partition and portal vein ligation for staged hepatectomy (ALPPS) has been suggested as a potential therapy for extensive bilobar liver tumors, although in some circumstances this technique may induce tumor progression, a fact still not well studied. Our aim was to study tumor hepatic progression induced by the first step of ALPPS in a WAG/Rij rat syngenic model of metastatic colorectal carcinoma by subcapsular CC531 cell line inoculation. ALPPS induced: tumor progression on deportalized lobe and metastases; expression of hepatic vasculogenic factors (HIF1-α and VEGF); and a dramatic increase of Kupffer cells (KCs) and tumor-associated macrophages (TAMs). Interestingly, KCs expressed COX-2 (M1 polarization), while TAMs expressed mainly arginase-1 (M2 polarization). ALPPS also induced a decrease of tumor-infiltrating lymphocytes and an increase of intrahepatic T lymphocytes. Thus, ALPPS technique seems to induce a hypoxic environment, which enhances hepatic HIF1-α and VEGF expression and may promote KCs and TAMs polarization. Consequently, the regenerative stimulus seems to be driven by a pro-inflammatory and hypoxic environment, in which M1 intrahepatic macrophages expressing COX-2 and T-Lymphocytes play a key role, facts which may be related with the tumor progression observed.

Hepatic Encephalopathy in Patients with Liver Cirrhosis before and after TIPS

Aim. To analyze the dynamics of hepatic encephalopathy after transjugular intrahepatic portosystemic shunting (TIPS). Material and Methods. It was analyzed the results of complex survey of 52 patients who underwent TIPS. Self-expanding stents 8–10 cm, diameter of 8–10 mm and stent-graft were applied for portosystemic shunt creation. Results. The two main complications of TIPS are hepatic encephalopathy progression and shunt’s malfunction. The increased degree of portosystemic encephalopathy in 18 months postoperatively was revealed in 3 (10%) patients. Symptoms of encephalopathy were eliminated and did not effect on the patients’ life quality after discharge. Conclusion. Assessment of encephalopathy’s degree and individual therapy in each patient significantly decrease the severity of encephalopathy postoperatively followed by improved life quality

Abstract P1-14-06: Selective internal radiation therapy (SIRT) with Yttrium-90 resin microspheres and FOLFOX/5FU chemotherapy in pre-treated breast cancer patients with liver metastases: A retrospective analysis of response rates, times to progression and survival of patients treated in Manchester UK between 2010 and 2016

Abstract Background: SIRT is a globally licensed technique of Radio-Embolization (RE) of hepatic tumors via intra-arterial infusion of β-particle emitting Yttrium-90 (Y-90) radio-labelled microspheres. It increases response rates and hepatic time to progression in metastatic colorectal cancer when used in combination with 5FU/Oxaliplatin (FOLFOX) chemotherapy with acceptable toxicity profile. FOLFOX gives a radio-sensitizing effect and also controls disease outside the liver. Breast cancer liver metastases (BCLM) patients often have extra-hepatic disease and respond to multiple lines of systemic therapy and SIRT is infrequently used. Methods and patients Between 2010 and 2016 we treated 25 BCLM patients with Y-90 SIRT. Receptor status: 20 ER+ve/HER-2 -ve, 3 ER-ve/HER-2 +ve, 2 triple -ve. Eleven patients had liver only disease with 14 also having known extra-hepatic disease. Average number of previous lines of therapy in metastatic setting: chemotherapy = 2.4; endocrine = 1. Sixty-four % patients had prior Capecitabine (n=16); 12% platinum (n=3, all Carboplatin). Twenty patients received chemotherapy with SIRT: 17 had modified FOLFOX6 (Oxaliplatin/bolus 5FU day1, infusional 5FU day 1-3 (46 hrs); 3 patients had Modified de Gramont style 5FU alone. Five patients had no chemotherapy. Sir-spheres were inserted on day 2 of FOLFOX with the 5FU infusion pump continuing to day 3. Further 2-weekly FOLFOX chemo cycles were at clinician's discretion: average number delivered 3.8. Four patients had the liver treated in two halves, approximately 6 weeks apart. One patient received SIRT only to half the liver. Patients were imaged with PET-CT/CT before and 2-3 months after SIRT. Retrospective case note review was performed and data correlated to evaluate tumor response (RR); hepatic and extra hepatic progression free survival (HPFS and EHPFS) and overall survival (OS). Accurate toxicity data was not recorded. Results Hepatic CT response rates: PR 56% (n=14), SD 28% (n=7) and PD 16% (n=4). Hepatic PET response rates: CR 32% (n=8), PR 40% (n=10), SD 12% (n=3), PD 16%(n=4). (Overall PET liver disease control rate = 84%). Eight patients (32%) had extra-hepatic PD at first assessment. Of them, 4 had PR, 2 SD and 2 PD in the liver at that assessment. Two HER-2 +ve patients had brain metastases as first sign of PD within 75 days, an area not previously screened. Of 16 pre-treated with Capecitabine, liver CT response rates: 62.5% PR, 18.75% SD (n=10,3). Post SIRT/FOLFOX, average number of therapy lines: 2 for chemo and 0.75 for endocrine, with 8 patients still alive at time of censoring. Median OS: 766 HPFS: 210 days (CI 140-286). Median EHPFS in patients with extra-hepatic disease: 152 days (CI 96-636). Conclusions SIRT with FOLFOX in previously treated BCLM patients produces high response rates, excellent tumor control and time to progression in the liver with good overall survival. It does not seem to decrease the ability to give further lines of chemotherapy and can be considered as an option for breast cancer patients with liver metastases. Citation Format: Wilson G, Mullamitha S, Bentley D, Bell J, Mullan D, Carter L, Chittalia A, Howell S, Laasch H-U, Westwood T, Jeans S, Tipping J, Ryder D, Farquharson F, Arumugam P, Sheen A, Rajashanker B, Armstrong A, Misra V, Manoharan P, Lawrance J. Selective internal radiation therapy (SIRT) with Yttrium-90 resin microspheres and FOLFOX/5FU chemotherapy in pre-treated breast cancer patients with liver metastases: A retrospective analysis of response rates, times to progression and survival of patients treated in Manchester UK between 2010 and 2016 [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-14-06.

The epigenetic writer LSD1 controls hepatic cell cycle progression by alteration of global expression profiles and protein signatures

The epigenetic writer LSD1 controls hepatic cell cycle progression by alteration of global expression profiles and protein signatures

Percutaneous hepatic perfusion with melphalan in uveal melanoma: A safe and effective treatment modality in an orphan disease.

BackgroundMetastatic uveal melanoma (UM) carries a poor prognosis; liver is the most frequent and often solitary site of recurrence. Available systemic treatments have not improved outcomes. Melphalan percutaneous hepatic perfusion (M‐PHP) allows selective intrahepatic delivery of high dose cytotoxic chemotherapy.MethodsRetrospective analysis of outcomes data of UM patients receiving M‐PHP at two institutions was performed. Tumor response and toxicity were evaluated using RECIST 1.1 and Common Terminology Criteria for Adverse Events (CTCAE) v4.03, respectively.ResultsA total of 51 patients received 134 M‐PHP procedures (median of 2 M‐PHPs). 25 (49%) achieved a partial (N = 22, 43.1%) or complete hepatic response (N = 3, 5.9%). In 17 (33.3%) additional patients, the disease stabilized for at least 3 months, for a hepatic disease control rate of 82.4%. After median follow‐up of 367 days, median overall progression free (PFS) and hepatic progression free survival (hPFS) was 8.1 and 9.1 months, respectively and median overall survival was 15.3 months. There were no treatment related fatalities. Non‐hematologic grade 3‐4 events were seen in 19 (37.5%) patients and were mainly coagulopathic (N = 8) and cardiovascular (N = 9).ConclusionsM‐PHP results in durable intrahepatic disease control and can form the basis for an integrated multimodality treatment approach in appropriately selected UM patients.

Ways to improve the results of surgical treatment for obstructive jaundice on the background of gall stone disease

The relevance of the problem of obstructive jaundice is caused primarily by an increase in the number of these patients, which reaches 22 % among persons with hepatopancreatoduodenal pathology. At the same time, nearly 50 % of patients seek surgical treatment late, which leads to severe morphological and biochemical changes in the liver, and hepatic progression to multiple organ failure. The analysis of the results of treatment in patients with obstructive jaundice on the background of cholelithiasis was performed. The study included 50 patients, who were treated surgically. They were divided into two equal groups, one of which in addition to standard treatment received L-lysine aescinat and glutargin. Research showed advantages of this treatment, an earlier elimination of symptoms in patients with hepatic impairment and, consequently, milder postoperative period.

Abstract No. 40DISTINGUISHED ABSTRACT - DAXX mutation is associated with poor response and shorter hepatic progression after hepatic artery embolization of neuroendocrine liver metastases

Abstract No. 40DISTINGUISHED ABSTRACT - DAXX mutation is associated with poor response and shorter hepatic progression after hepatic artery embolization of neuroendocrine liver metastases

Response rates of hepatic arterial infusion pump therapy in patients with metastatic colorectal cancer liver metastases refractory to all standard chemotherapies.

To evaluate the role of hepatic arterial infusion (HAI) in patients with metastatic colorectal cancer (mCRC) liver metastases (LM) refractory to oxaliplatin, irinotecan, and fluorouracil-based treatments. A search identified patients with mCRC treated after tumor progression on at least three standard systemic therapies. One hundred and ten patients met criteria for inclusion (i.e., progression on at least three standard agents). Fifty seven patients had LM-only and 53 patients had LM and low volume extrahepatic metastases (LME). Patients with LM-only and LME had a response rate (RR) of 33% and 36%, median survival of 20 months and 11.4 months, respectively. Patients with LM-only had progression free survival of 6 months and hepatic progression free survival of 7.56 months. In a secondary analysis, 46 patients were RECIST-refractory to all standard therapies: LM-only (n = 24) and LME (n = 22). LM-only and LME had a RR of 29% and 36%, and median survival 17.2 months and 9.1 months, respectively. Patients with refractory mCRC LM can achieve a response to HAI resulting in antitumor activity and improvement in survival. Responses are rarely seen in such heavily treated patients with systemic therapy alone, suggesting a regional directed approach is useful. J. Surg. Oncol. 2016;114:655-663. © 2016 Wiley Periodicals, Inc.

Phase Ib trial of gemcitabine with yttrium-90 in patients with hepatic tumors of pancreatobiliary origin.

460 Background: The rationale for combining Gemcitabine (G) with Yttrium-90 (Y90) is based on G being a potent radio sensitizer and activity of Y90 against liver tumors of pancreatobiliary histology. Therefore, a safety and efficacy trial of adding G to Y90 is required. Methods: Eligibility: Chemo-naïve patients with histologic diagnosis of unresectable PC or CC with liver predominant disease. Design: Open label phase I design with 3+3 G dose escalation. Induction G on Day 1 followed by Y90 on Day 2 and subsequent pre-assigned dose levels of G until week 12. Primary objective: To determine the maximal tolerated dose of G that can be used in combination with Y90. Secondary objectives: To characterize the toxicity, evaluate hepatic progression free survival (HPFS); determine tumor response rate using RECIST and PERCIST criteria; determine the progression free survival (PFS) and overall survival (OS). Correlative Imaging: 18-FDG PET/CT with contrast at baseline and 12 weeks. Results: 14 patients were recruited and 8 met the inclusion criteria. Seven out of eight patients tolerated the dose escalation regime of G (dose level 1-400 and dose level 2-600mg/m2). All the patients developed grade 1 toxicities (Hepatobiliary 25%, Bone marrow 25%, Fatigue 100%). Three patients (37.5 %) had grade 2 hepatobiliary toxicity and one patient (12.5 %) had grade 3 hepatobiliary toxicity, which required short-term hospitalization. No radiation pneumonitis, gastrointestinal ulceration, or procedure-related mortality occurred. Six patients (75%) developed grade 1 toxicity (fatigue). All of the patients had SD in the liver by RECIST; the objective response rate was 62.5% by PERCIST (CR12.5%, PR50%, SD25% PD12.5%). Overall objective response rate was 0% by RECIST (SD62.5%, PD37.5%); and 50% for PERCIST (CR12.5%, PR37.5%, SD12.5%, PD37.5%). The median OS from diagnosis was 13.8 months (95% CI, 9.65 to 26.29 months) and from Y90 therapy 10.9 months (95% CI, 6.47 to 22.39 months). PFS was 6.92 months (95%CI, 4.37-16.5 months) and HPFS of 8.72 months (95%CI, 4.48-19.36 months). Conclusions: In patients with hepatic tumors of pancreatobiliary origin, Gemcitabine at 600mg/m2 with Y90 therapy appears to be a viable and safe therapy. Clinical trial information: NCT01434459.

Abstract A138: Identification of key immune regulators that control obesity-induced liver inflammation and diseases

Abstract Obesity has become a major risk factor for a number of human diseases, including cancer. Amongst different types of malignancies, obesity appears to have the highest association-rate with hepatocellular carcinoma (HCC), the dominant form of primary liver cancer. Obesity-induced sterile inflammation is the key switch mediating the transition from hepatic steatosis to steatohepatitis (non-alcoholic steatohepatitis, NASH) and HCC. However, the molecular mechanism underlying obesity-induced hepatic inflammation remains poorly understood. We show that fat accumulation increases liver damage and release of DAMP (damage-associated molecular patterns) from dying hepatocytes, to amplify inflammation and accelerate hepatic disease progression. These DAMP induce mitochondrial reactive oxygen species (mtROS) in macrophages, which direct inflammatory cytokine/chemokine production in a manner that requires activation of a calcium permeable channel, TRPM2 (transient receptor potential melastatin 2). Blockade of mtROS generation, removal of extracellular calcium or ablation of TRPM2 expression in macrophages abolished DAMP-induced inflammatory cytokine/chemokine production, suggesting that a “mtROS-TRPM2” pathway drives DAMP-induced inflammation. Moreover, we identified HMGB1 as the key DAMP released from lipid-damaged hepatocytes. By using HMGB1 neutralizing antibody, we found it suppressed HMGB1 expression in the liver of MUP-uPA mice (an animal model for human NASH), and markedly attenuated liver damage, accumulation of lipid droplets, inflammation, and fibrosis, which represent typical features of human NASH. These results also suggest that HMGB1 is a key component of a vicious autoregulatory cycle triggered by HFD consumption, that mains ER stress and liver inflammation, as well as elevated HMGB1 expression and release. Citation Format: Zhenyu Zhong, Atsushi Umemura, Shuang Liang, Michael Karin. Identification of key immune regulators that control obesity-induced liver inflammation and diseases. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A138.

Acquired BRAF inhibitor resistance: A multicenter meta-analysis of the spectrum and frequencies, clinical behaviour, and phenotypic associations of resistance mechanisms

BackgroundAcquired resistance to BRAF inhibitors (BRAFi) is a near-universal phenomenon caused by numerous genetic and non-genetic alterations. In this study, we evaluated the spectrum, onset, pattern of progression, and subsequent clinical outcomes associated with specific mechanisms of resistance. MethodsWe compiled clinical and genetic data from 100 patients with 132 tissue samples obtained at progression on BRAFi therapy from 3 large, previously published studies of BRAFi resistance. These samples were subjected to whole-exome sequencing and/or polymerase chain reaction-based genetic testing. ResultsAmong 132 samples, putative resistance mechanisms were identified in 58%, including NRAS or KRAS mutations (20%), BRAF splice variants (16%), BRAFV600E/K amplifications (13%), MEK1/2 mutations (7%), and non-mitogen-activated protein kinase pathway alterations (11%). Marked heterogeneity was observed within tumors and patients; 18 of 19 patients (95%) with more than one progression biopsy had distinct/unknown drivers of resistance between samples. NRAS mutations were associated with vemurafenib use (p = 0.045) and intracranial metastases (p = 0.036), and MEK1/2 mutations correlated with hepatic progression (p = 0.011). Progression-free survival and overall survival were similar across resistance mechanisms. The median survival after disease progression was 6.9 months, and responses to subsequent BRAF and MEK inhibition were uncommon (2 of 15; 13%). Post-progression outcomes did not correlate with specific acquired BRAFi-resistance mechanisms. ConclusionsThis is the first study to systematically characterise the clinical implications of particular acquired BRAFi-resistance mechanisms in patients with BRAF-mutant melanoma largest study to compile the landscape of resistance. Despite marked heterogeneity of resistance mechanisms within patients, NRAS mutations correlated with vemurafenib use and intracranial disease involvement.