Size Of Liver Metastases Research Articles

Liver metastases and peritoneal metastases and response to checkpoint inhibitors in metastatic colorectal cancer with microsatellite instability.

There have been conflicting reports on the predictive impact of metastatic disease sites on the response to checkpoint inhibitors (CPI) in microsatellite instability (MSI) metastatic colorectal cancers (mCRC). Recent studies have highlighted peritoneal metastases, ascites, and liver metastases as possible indicators of resistance to CPI. We performed a detailed analysis of high microsatellite instability (MSI-H) mCRC treated with programmed cell death (PD-1) or PD-1/cytotoxic T-lymphocyte-associated protein 4 CPI in a single center. Overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and stable disease but with complete pathological response upon resection (SDcPR) were analyzed by the presence of liver metastases, peritoneal metastases, or absence of either. The impact of number and size of liver metastases on clinical outcomes were also interrogated. Thirty-five patients with MSI mCRC were included in the analysis. Patients with peritoneal metastatic disease had lower ORR and shorter PFS compared to patients without liver and peritoneal metastases. Contrary to recent reports, ORR and ORR + SDcPR rates were high in patients with liver metastases, at 58% and 66%, respectively. In the liver metastases category, a better response rate was noted for patients with<5 lesions compared to patients with more than 5 lesions. Patients who responded had a higher median tumor mutation burden than patients with progressive disease. In MSI mCRC, no single clinical characteristic was sufficient to preclude CPI response. Peritoneal metastatic disease was associated with numerically lower ORR and shorter PFS. In contrast, liver metastases do not predict poor outcome.

Survival benefit of adjuvant chemotherapy based on molecular residual disease detection in resected colorectal liver metastases: subgroup analysis from CIRCULATE-Japan GALAXY

The prognostic role of circulating-tumor DNA (ctDNA)-based molecular residual disease (MRD) detection and its utility for postsurgical risk-stratification has been reported in colorectal cancer. In this study, we explored the use of ctDNA-based MRD detection in patients with colorectal liver metastases (CLM), for whom the survival benefit of adjuvant chemotherapy (ACT) after surgical resection remains unclear. Patients with CLM without extrahepatic disease from GALAXY study (UMIN000039205) were included. The disease-free survival (DFS) benefit of ACT was evaluated in MRD-positive and -negative groups after adjusting for age, gender, number and size of liver metastases, RAS status, and previous history of oxaliplatin for primary cancer. ctDNA was detected using a personalized, tumor-informed 16-plex mPCR-NGS assay. ctDNA-based MRD status was evaluated 2 to 10 weeks after curative surgery, before the start of ACT. Among 6,061 patients registered in GALAXY, 190 surgically resected CLM patients without any preoperative chemotherapy were included with a median follow-up of 24 (1-48) months. ctDNA positivity in the MRD window was 32.1% (61/190). ACT was administered to 25.1% (48/190) of patients. In the MRD-positive group, 24-month DFS was higher for patients treated with ACT (33.3% vs. not reached, adjusted HR: 0.07, P <0.0001); whereas no benefit of ACT was seen in the MRD-negative group (24-month DFS: 72.3% vs. 62.2%, adjusted HR: 0.68, P =0.371). Multivariate analysis showed that the size of liver metastases (HR: 3.94, P =0.031) was prognostic of DFS in the MRD-positive group. However, in the MRD-negative group, none of the clinicopathological factors were prognostic of DFS. Our data suggest that ACT may offer notable clinical benefits in MRD-positive patients with CLM. MRD status-based risk-stratification could be potentially incorporated in future clinical trials for CLM.

Patterns and Predictors of Recurrence After Curative Resection of Colorectal Liver Metastasis (CRLM).

Our study aims to determine the predictors and patterns of relapses after curative colorectal liver metastasis (CRLM) resection. A single-centre, retrospective study of CRLM patients operated between 2010 and 2022 was performed. The site of first recurrence was either hepatic (marginal (≤ 1cm) or extramarginal), extrahepatic, or both. Factors that predicted relapse patterns and overall survival were determined by multivariable Cox regression analysis with backward elimination of variables. The study consisted of 258 patients, with a similar proportion of synchronous (144; 56%) and metachronous(114; 43%) metastasis. At a 43-month median follow-up, 156 patients (60.4%) developed recurrences with 33 (21.1%) in the liver, 62(24.03%) extra-hepatic recurrences, and 58 (22.48%) having both. Isolated marginal liver relapses were seen in seven (9.89%) liver recurrence patients. The median overall and relapse-free survivals were 38months (30-54) and 13months (11-16), respectively. The 3-year liver-relapse-free survival was 54.4% (44.9-60.6). Size of liver metastases > 5cm (HR 2.06 (1.34-3.17), involved surgical margins (HR 2.16 (1.27-3.68)), and adjuvant chemotherapy (HR 1.89 (1.07-3.35)) were predictors of hepatic recurrences. Node positivity of primary (HR 1.61 (1.02-2.56)), presence of baseline extra-hepatic metastases (HR 0.30 (0.18-0.51)), size of liver metastases > 5cm (HR 2.02 (1.37-2.99)), poorly differentiated histology (HR 2.25 (1.28-3.49)), presence of LVI (HR 2.25 (1.28-3.94)), and adjuvant chemotherapy (HR 2.15 (1.28-3.61)) were predictors of extra-hepatic recurrences. The study found majority relapses occurred at extrahepatic sites whilst isolated marginal recurrences were few. The consistent predictors of recurrence were size and inability to deliver adjuvant therapy. A tailored adjuvant therapy might improve outcomes after liver metastasectomy in colorectal cancers.

CT versus MR guidance for radiofrequency ablation in patients with colorectal liver metastases: a 10-year follow-up favors MR guidance.

To compare the results of CT- vs MR-guided radiofrequency ablation (RFA) of liver metastases (LM) from colorectal cancer after 10years of follow-up in an observational, retrospective, and multicentric study. A total of 238 patients with 496 LM were treated with RFA either with CT (CT group) or magnetic resonance (MR group) guidance. Every ablated LM was assessed and followed up with diagnostic MRI. Technical success, technique efficacy, predictive factors, recurrence rates, and overall survival were assessed. The CT group comprised 143 patients and the MR group 77 patients. Eighteen patients underwent ablation with both modalities. Technical success per patient and per lesion was 88% and 93% for CT and 87% and 89.6% for MR, and technique efficacy was 97.1% and 98.6% for CT and 98.7% and 99.3% for MR respectively. Local recurrence following the first ablation (primary patency) occurred in 20.1% (CT) vs 4.6% (MR) (p < 0.001). Residual liver tumor, size of LM, and advanced N and M stage at initial diagnosis were independent predictors for overall survival in both groups. The median overall survival measured from first RFA treatment was 2.6years. The 1-year, 5-year, and 10-year survival were 85.9%, 25.5%, and 19.1% respectively. The MR group had significantly better local control compared to the CT group. There was no significant difference in patient survival between the two groups. MR-guided radiofrequency ablation of colorectal liver metastases is safe and effective, and offers better local control than CT-guided ablation. • Imaging modality for radiofrequency ablation guidance is an independent predictor of local recurrence in colorectal liver metastases. • MR-guided radiofrequency ablation achieved better local control of liver metastases from colorectal cancer than CT-guided. • The number and size of liver metastases are, among others, independent predictors of survival. Radiofrequency ablation with MR guidance improved clinical outcome but does not affect survival.

FRI603 Treatment Of Severe Refractory Hypoglycemia Due To Malignant Insulinoma With A Novel Anti-insulin Receptor Antibody

Abstract Disclosure: S. Osataphan: None. M. Vamvini: None. E.D. Rosen: Consulting Fee; Self; Novartis Pharmaceuticals. L. Pei: None. N. Erlikh: None. G. Singh: None. P. Dhorajiya: None. J. Parker: None. J.M. Dreyfuss: None. A. Rattani: Stock Owner; Self; Vertex Pharmaceuticals, Provention Bio, Bluebird Bio, Agenus, MacroGenics, Immunity Bio, Mirati Therapeutics, Actinium Pharmaceuticals, Bausch Health Companies, Compass Therapeutics, Magenta Therapeutics. M. Patti: Advisory Board Member; Self; Fractyl Laboratories. Consulting Fee; Self; AstraZeneca, Hanmi Pharmaceuticals, MBX. Grant Recipient; Self; Dexcom. Severe hypoglycemia caused by malignant insulinoma is often resistant to medical therapy targeting both tumor burden and insulin secretion. We report a patient who developed severe, treatment-resistant hypoglycemia after receiving 177lutetium-DOTATATE (Lu-177). Hypoglycemia was completely ameliorated after treatment with RZ358, a human monoclonal antibody that functions as a negative allosteric modulator of the insulin receptor, reducing insulin signaling. This 55 year old man presented with abdominal pain, fatigue, and weight loss; imaging showed a 1.8 cm pancreatic tail mass and numerous hepatic lesions. Liver biopsy demonstrated well-differentiated pancreatic neuroendocrine tumor, WHO Grade 2, and pathogenic MEN1 mutation. Following one year of octreotide therapy, both pancreatic and hepatic tumors increased in size, prompting Lu-177 therapy. Two days after the first dose, the patient became unresponsive, with capillary glucose 20 mg/dL. He developed recurrent neuroglycopenia on day 8, with venous glucose 41 mg/dL, insulin 45 µIU/mL, C-peptide 6.5 ng/mL and proinsulin 453 pmol/L, requiring intensive care unit admission for for intravenous glucose. High-dose diazoxide, everolimus, dexamethasone, glucagon, pasireotide, or enteral feeding did not produce a response. Despite multiple therapies, neuroglycopenia required frequent dextrose boluses and continuous intravenous glucose (up to 30 g/hr of 50% dextrose); up to 58% of sensor glucose was below 70 mg/dL and 19% below 54 mg/dL over 24 hours. CT imaging 1 month after Lu-177 showed significant reduction in liver metastases size. Given the severity of hypoglycemia despite tumor regression, we considered treatment with RZ358, a human monoclonal antibody that acts as a negative allosteric modulator of the insulin receptor, inducing insulin resistance. We obtained emergency use authorization from the FDA, approval from the local Institutional Review Board, and written informed consent. Following a 6 mg/kg dose of RZ358, there was transient worsening of hypoglycemia accompanied by an 8-fold increase in insulin, potentially due to reduced insulin clearance. After dose increase to 9 mg/kg weekly, glucose infusion was weaned. Metabolic stability was achieved after 6 doses, allowing a second dose of Lu-177 and eventual discharge. Diazoxide was discontinued, steroid doses were reduced, and RZ358 dosing was reduced to every 3-4 weeks. A third dose of Lu-177 was administered without complications. Despite elevated insulin (537 uIU/mL), C-peptide (10.1 ng/mL), and proinsulin (634.0 pmol/L), he remains free of level 3 hypoglycemia. No adverse effects have been observed. In summary, the anti-insulin receptor monoclonal antibody RZ358 effectively controlled hypoglycemia refractory to multiple other therapies, allowing restoration of normoglycemia and enabling additional successful cancer therapy. Presentation: Friday, June 16, 2023

Proposal of early CT morphological criteria for response of liver metastases to systemic treatments in gastroenteropancreatic neuroendocrine tumors: Alternatives to RECIST.

RECIST 1.1 criteria are commonly used with computed tomography (CT) to evaluate the efficacy of systemic treatments in patients with neuroendocrine tumors (NETs) and liver metastases (LMs), but their relevance is questioned in this setting. We aimed to explore alternative criteria using different numbers of measured LMs and thresholds of size and density variation. We retrospectively studied patients with advanced pancreatic or small intestine NETs with LMs, treated with systemic treatment in the first-and/or second-line, without early progression, in 14 European expert centers. We compared time to treatment failure (TTF) between responders and non-responders according to various criteria defined by 0%, 10%, 20% or 30% decrease in the sum of LM size, and/or by 10%, 15% or 20% decrease in LM density, measured on two, three or five LMs, on baseline (≤1 month before treatment initiation) and first revaluation (≤6 months) contrast-enhanced CT scans. Multivariable Cox proportional hazard models were performed to adjust the association between response criteria and TTF on prognostic factors. We included 129 systemic treatments (long-acting somatostatin analogs 41.9%, chemotherapy 26.4%, targeted therapies 31.8%), administered as first-line (53.5%) or second-line therapies (46.5%) in 91 patients. A decrease ≥10% in the size of three LMs was the response criterion that best predicted prolonged TTF, with significance at multivariable analysis (HR 1.90; 95% CI: 1.06-3.40; p = .03). Conversely, response defined by RECIST 1.1 did not predict prolonged TTF (p = .91), and neither did criteria based on changes in LM density. A ≥10% decrease in size of three LMs could be a more clinically relevant criterion than the current 30% threshold utilized by RECIST 1.1 for the evaluation of treatment efficacy in patients with advanced NETs. Its implementation in clinical trials is mandatory for prospective validation. Criteria based on changes in LM density were not predictive of treatment efficacy. CLINICAL TRIAL REGISTRATION: Registered at CNIL-CERB, Assistance publique hopitaux de Paris as "E-NETNET-L-E-CT" July 2018. No number was assigned. Approved by the Medical Ethics Review Board of University Medical Center Groningen.

Safety and early biologic effects of phase 1 PERIO-01 trial of pressure-enabled drug delivery (PEDD) of TLR9 agonist SD-101 and immune checkpoint inhibition (ICI) in uveal melanoma metastatic to the liver (MUM).

2521 Background: Delivery barriers due to intratumoral pressure and immunosuppression related to myeloid-derived suppressor cells (MDSC) in liver tumors have created challenges for immunotherapy. TLR9 agonists seem to improve response to ICI. PERIO-01 is a first-in-man trial of PEDD of SD-101 using hepatic arterial infusion (HAI) with ICI in MUM. Methods: PERIO-01 is an open-label phase 1 trial of SD-101 given by HAI in MUM (NCT04935229). The study consists of dose-escalation cohorts of SD-101 alone (Cohort A), with nivolumab (Cohort B), or nivolumab + ipilimumab (Cohort C). SD-101 is delivered over 2 cycles, with 3 weekly doses per cycle. Blood, liver metastasis (LM) and normal liver biopsies are collected for correlative studies. Results: At data cutoff, 33 patients were enrolled, 30 of whom received at least one dose of SD-101, 13 in Cohort A (2, 4, and 8 mg), 15 patients in Cohort B (2 mg and 4 mg) and 2 patients in Cohort C (2 mg). The median age was 63 years of equal gender. Only 3 patients were treatment-naïve and 2 were HLA-A*-02:01+ who received prior tebentafusp. Nine subjects had 4-7 LM and 4 had &gt; 10. The median index LM size was 4.7 cm. Only one patient experienced a grade ≥3 adverse event (AE) related to SD-101, which was increased liver enzymes. All AEs related to cytokine release syndrome have been low-grade with the most common being fever (9), chills (5), and dizziness (4). Treatment resulted in high liver drug levels (median at 2 mg = 1540 ng/g and 8 mg = 2325 ng/g, p = 0.035), with only transient exposure in the periphery ( &lt; 4 hours) and a maximum peak serum level of 554 mg/ml 30 minutes post-infusion. Increases in serum IL-18 and IFNγ were noted, with highest levels at 8 mg. Expansion of natural killer cells were detected in 9 of 10 patients from flow cytometry data peripherally. Monocytic MDSC levels were decreased in 5 of 5 patients on immunofluorescence, and NanoString analysis revealed decreases in ARG-1 and IDO-1 gene levels up to 100 days from initial treatment. Broad immunostimulatory gene expression changes were noted in tumor and normal liver following SD-101, including increases in IFNB1 and IL-9. Using the available samples from 13 patients, 7 of 10 had decrease in ctDNA, with complete clearance in 3, along with circulating tumor cell decreases in 6 of 13. In cohort B at 2 mg, 5 of 6 with available response data have stable disease with a median duration of disease control of 12 weeks (range = 7.5-24) at data cutoff. Conclusions: HAI of SD-101 has been well tolerated and associated with encouraging immunologic activity. Evidence of biologic effects at the lower doses of SD-101 with nivolumab is encouraging and enrollment with escalation continues in Cohorts B and C. Clinical trial information: NCT04935229 .

Abstract 485: Hypoxia inducible factor (HIF) inhibitor 64B has superior anti-tumor effects compared to two different tyrosine kinase inhibitors when tested in mouse models of uveal melanoma

Abstract Uveal melanomas (UMs) arise from melanocytes along the uveal tract and are distinct from cutaneous melanomas, with different molecular events in their pathogenesis. While primary treatment generally results in good local control, UMs spread systemically in approximately 50% of patients, most commonly to the liver. Patients who develop metastases are more likely to express the hypoxia-induced transcription factor HIF-1α and the HIF-regulated genes CXCR4 and c-Met when compared to patients who do not develop metastatic disease1, suggesting that blocking HIF function might be clinically beneficial for the management of UM, a tumor type that fails to respond to treatments that are effective for treating cutaneous melanoma. 64B is a small molecule therapeutic that inhibits the function of hypoxia inducible factors (HIFs) by disrupting the recruitment of the transcription co-factor paralogs, p300/CBP, while leaving intact p300/CBP’s ability to function with multiple other transcription factors. As a consequence, 64B is well tolerated and blocks transcription of multiple genes that help tumor cells survive and spread, including genes involved in angiogenesis, multidrug resistance, invasion and metastases. Using several different UM tumor cell lines implanted in the uveal tract of mice, we previously showed that 64B given systemically inhibits primary tumor growth and metastases1. We now compare the anti-cancer efficacy of 64B to two different tyrosine kinase inhibitors (TKIs) that are in clinical testing for UM, sunitinib and selumetinib. Sunitinib is a TKI that suppresses the function of the growth factor receptors c-kit and VEGFR, proteins that are highly expressed in UM. Selumetinib is a highly selective MEK1/2 inhibitor, targeting the MEK pathway that is activated in UM due to the GNAQ/11 activation that occurs in about 85% of UMs. Human UM cells (92.1; GNAQ Q209P mutant) were implanted in the flank of nude mice, and systemic treatment (i.p.) with 64B was started once the s.c tumor reached 100 mm3. 64B was far superior to either sunitinib or selumetinib at causing a regression in tumor size and in reducing the number and size of liver metastases. The metastases that were observed in 64B-treated animals were very small and did not show evidence of tumor vascularization, unlike the control tumors which were much larger and were vascularized. The tumor-bearing animals receiving 64B were behaviorally normal and were healthier than control mice or mice receiving either sunitinib or selumetinib, some of which died in the non-64B groups. The efficacy of 64B at causing tumor regression and reducing metastases combined with its safety profile support advancing 64B to clinical testing for metastatic UM. 1 Dong L et al, Clin Cancer Res. 2019;25(7):2206-18. Citation Format: Hua Yang, Hans E. Grossniklaus, Erwin G. Van Meir, Margaret K. Offermann. Hypoxia inducible factor (HIF) inhibitor 64B has superior anti-tumor effects compared to two different tyrosine kinase inhibitors when tested in mouse models of uveal melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 485.

Characterization of liver function tests (LFTs) following tebentafusp (tebe) in previously treated (2L+) metastatic uveal melanoma (mUM) patients (pts).

e21513 Background: Tebe is a bispecific gp100-targeted T cell receptor fusion protein that can redirect polyclonal T cells to target gp100+ cells leading to T cell activation and release of inflammatory mediators. Hepatocytes do not express gp100 and tebe did not redirect T cells against normal hepatocytes in preclinical in vitro studies. However, since most mUM pts have liver metastases, tebe may result in secondary effects from localized tumor-related inflammation. Here we describe LFT kinetics and outcomes for pts in the IMCgp100-102 study (NCT02570308). Methods: 127 HLA-A*02:01+ pts with 2L+ mUM received tebe, administered weekly at the RP2D following intra-patient dose escalation (C1D1: 20μg; C1D8: 30μg; C1D15+: 68μg). Pts were eligible if ALT/AST ≤ 3 x ULN and bilirubin ≤ 1.5 x ULN. LFTs were measured at baseline (BL) and weekly prior to each dose using local laboratories. AE grading was based on CTCAE v4.03. This analysis was conducted on the primary analysis snapshot dated 04Jun20. Results: At BL,125/127 (98%) pts had ALT/AST ≤ grade(G)1 and 122/127 (96%) had liver metastasis. 68/127 (54%) had an increase in post-BL grade for ALT, AST or both. Of these 48/68 (71%) increased to G1, 9/68 (13%) to G2, 7/68 (10%) to G3, and 4/68 (6%) to G4. 67 of these 68 pts (99%) had liver metastasis and most had largest liver metastasis &gt; 3cm (38 pts &gt; 3 cm, 29 pts &lt; 3cm and 1 pt without). ALT/AST increases occurred early in treatment in 36/68 (53%) including at Dose 1 (12/68; 18%), Dose 2 (10/68; 15%), or Dose 3 (14/68; 21%). In the other 32/68 pts (47%), ALT/AST increases occurred at or after Dose 4 (4-65), and most of these events (21/32; 66%) were associated temporally with increase in size of liver metastases. Among the 11 pts with G3/4 ALT/AST increases post-BL, most pts experienced these events early (Doses 1-3) (8/11; 73%) and in the context of either increase in size of liver metastases / disease progression or biliary obstruction (9/11; 82%). Most pts, 60/68 (88%), continued treatment despite an increase in ALT/AST grade. Among 8 pts who discontinued treatment, 3 were due to disease progression and 3 were due to adverse events. Median time for ALT/AST to return to BL was 9 days and there were no temporal increases in albumin or INR. Conclusions: Approximately 1/2 of tebe treated pts experienced an increase in post-BL CTCAE grade for ALT/AST. Among these pts, most ALT/AST increases were mild. Most of the pts with G3/4 ALT/AST increase (9/11) were explained by increase in size of liver metastases or biliary obstruction. Increase in LFT are not unusual at time of disease progression in mUM given high frequency of liver metastases. In summary, ALT/AST increases occurred early in about half of the pts, were generally self-limiting, permitted treatment to continue, and did not appear to impact liver synthetic function (INR/Albumin). Clinical trial information: NCT02570308.

Oncolytic Herpes Simplex Virus Type 2 Can Effectively Inhibit Colorectal Cancer Liver Metastasis by Modulating the Immune Status in the Tumor Microenvironment and Inducing Specific Antitumor Immunity.

Although colorectal cancer is the leading cause of death in patients with liver metastases, there are no efficient treatments available. Oncolytic virus therapy, a new type of tumor therapy, has become a potential solution. With the goal of improving the treatment of advanced colorectal cancer, we applied oncolytic herpes simplex virus type 2 (oHSV2) in a mouse model of colorectal cancer with liver metastasis. Compared with the control, oHSV2 effectively inhibited the growth of subcutaneous primary tumors, significantly reduced the number and size of liver metastases, and prolonged the median survival time of the mice. In addition, neutrophils, natural killer (NK) cells, T cells, B cells, and cytokines in the tumor microenvironment and the body were all activated, and their frequencies increased significantly. Moreover, the proportion of immunosuppressive myeloid-derived suppressor cells decreased. oHSV2 treatment, which establishes an effective long-term antitumor immune response, is strongly resistant to rechallenge by the same tumor. Our data show that oHSV2 can effectively kill the primary tumor and attack distal and metastatic tumors by inducing immune responses, resulting in lasting antitumor efficacy and preventing tumor recurrence. It is believed that oHSV2 has good clinical application prospects.

Incidentally Detected Liver Metastases during Pancreas Contrast-enhanced Ultrasound

Abstract Purpose: The purpose of current study was to investigate the value of the late-phase enhancement features of pancreas contrast-enhanced ultrasound (CEUS) in the detection of liver metastases in patients with pancreatic ductal adenocarcinomas (PDAC). Methods: From October 2020 to March 2021, 86 patients were prospectively enrolled. The gold standard of liver metastatic and PDAC lesions were based on histopathologically diagnoses and multiple imaging modalities results. B-mode ultrasound (BMUS) was performed to detect suspected liver metastases before CEUS. During the late phase of pancreas CEUS, the entire liver was scanned again to detect hypoenhanced liver metastases. Liver metastases were confirmed by biopsy and histopathological results. The number and size of liver metastases detected by BMUS and during CEUS late phase were recorded and compared. Results: Suspected liver metastases were detected in 14 patients by BMUS (n = 23). During the late phase of CEUS, hypoenhanced liver metastases were detected in 23 patients (n = 87). When compared with BMUS, whole-liver scan during the late phase of CEUS detected more isoechoic, small, or superficially located lesions. Compared with BMUS, the specificity, sensitivity, positive predictive value, and negative predictive value of CEUS in diagnosing of liver metastases in PDAC patients were significantly improved (96.72% vs. 100%, 48% vs. 92%, 85.71% vs. 100%, and 83.10% vs. 96.83%, respectively) (P &lt; 0.05). Conclusion: The late phase whole liver scan during CEUS of pancreas helps to detect more liver metastases, which is important for further clinical decision-making.

Benefits of simultaneous laparoscopic colorectal surgery and liver resection for colorectal cancer with synchronous liver metastases: Retrospective case-matched study

IntroductionLaparoscopic surgery for colorectal cancer and liver tumors are accepted as alternative procedure to open surgery. However, few studies reported outcomes of simultaneous laparoscopic surgery of these two procedures. The aim of this study was to compare short-term outcomes between laparoscopic and open approach. Materials and methodsBetween June 2010 to December 2019, simultaneous laparoscopic cases were retrospectively matched (1:2) to open cases. Peri-operative and short-term outcomes were compared between both groups. ResultsTwelve patients in laparoscopic group were matched to 24 patients in open group according to age, gender, body mass index, american society of anesthesiologists physical status, preoperative laboratory data, number and size of liver metastases and extent of colorectal and liver resection, Most patients in each group had left-sided colon or rectal cancer and underwent wedge liver resection. The mean number of liver metastases was 1.3 vs 1.5 and size of liver metastases was 2.2 ± 1.4 vs 2.7 ± 1.1 cm in laparoscopic compared to open group. Estimated blood loss and length of hospital stay were significantly lower in laparoscopic group. However, operative time was significantly longer in laparoscopic group. Peri-operative complication was not significant difference between both groups and there was no mortality. ConclusionSimultaneous laparoscopic colorectal surgery and minor liver resection is feasible and safe. Laparoscopic approach has better peri-operative outcome in term of shorter length of hospital stay compared to open approach.

The lack of selection criteria for surgery in patients with non-colorectal non-neuroendocrine liver metastases

BackgroundThe benefit of surgery in patients with non-colorectal non-neuroendocrine liver metastases (NCRNNELM) remains controversial. At the population level, several statistical prognostic factors and scores have been proposed but inconsistently verified. At the patient level, no selection criteria have been demonstrated to guide individual therapeutic decision making. We aimed to evaluate potential individual selection criteria to predict the benefit of surgery in patients undergoing treatment for NCRNNELM.MethodsData for 114 patients undergoing surgery for NCRNNELM were reviewed. In this population, we identified an early relapse group (ER), defined as patients with unresectable recurrence < 1 year postoperatively who did not benefit from surgery (N = 28), and a long-term survival group (LTS), defined as patients who were recurrence-free ≥ 5 years postoperatively and benefited from surgery (N = 20). Clinicopathologic parameters, the Association Française de Chirurgie (AFC) score, and a modified 4-point Clinical Risk Score (mCRS) (excluding CEA level) were analyzed and compared between LTS and ER groups.ResultsThe majority of patients were female and a majority had an ASA score ≤ 2 at the time of liver surgery. The median age was 55 years. Almost half of the patients (46%) presented with a single-liver metastasis. Intermediate- and low-risk AFC scores represented 40% and 60% of the population, respectively. Five- and 10-year overall survival (OS) and disease-free survival (DFS) rates were 56% and 27%, and 30% and 12%, respectively. Negative prognostic factors were the size of liver metastases > 50 mm and delay between primary and NCRNNELM <24 months for OS and DFS, respectively. AFC score was not prognostic while high-risk mCRS (scores 3–4) was predictive for the poorer OS. The clinicopathologic parameters were similar in the ER and LTS groups, except the presence of N+ primary tumor, and the size of liver metastases was significantly higher in the ER group.ConclusionIn patients with resectable NCRNNELM, no predictive factors or scores were found to accurately preoperatively differentiate individual cases in whom surgery would be futile from those in whom surgery could be associated with a significant oncological benefit.

Hepatic resection for breast cancer liver metastases: Impact of intrinsic subtypes

IntroductionThe role of surgery for breast cancer liver metastases (BCLM) remains controversial. This study aimed to analyze survival in patients treated with hepatectomy plus systemic therapy or systemic therapy alone for BCLM and to determine selection factors to guide surgical therapy. Materials and methodsPatients who underwent hepatectomy plus systemic therapy (n = 136) and systemic therapy alone for isolated BCLM (n = 763) were compared. Overall survival (OS) was analyzed after propensity score matching. Intrinsic subtypes were defined as: luminal A (estrogen receptor [ER]+ and/or progesterone receptor positive [PR]+, human epidermal growth factor receptor 2 [HER2]–), luminal B (ER and/or PR+, HER2+), HER2-enriched (ER and PR–, HER2+), and basal-like (ER, PR, HER2–). ResultsAfter hepatectomy, independent predictors of poor OS were number and size of liver metastases, and intrinsic subtype (hazard ratios, 1.11, 1.16, and 4.28, respectively). Median OS was 75 and 81 months among patients with luminal B and HER2-enriched subtypes, compared with 17 and 53 months among patients with basal-like and luminal A subtypes (P < .001). Median progression-free survival (PFS) was 60 months with the HER2-enriched subtype, compared with 17, 16, and 5 months with luminal A, luminal B, and basal-like subtypes, respectively (P < .001). After propensity score matching, 5-year OS rates were 56% vs. 40% in the surgery vs. systemic therapy alone groups (P = .018). ConclusionSurgical resection of BCLM yielded higher OS compared with systemic therapy alone and prolonged PFS among patients with the HER2-enriched subtype. These findings support the use of surgical therapy in appropriately selected patients, based on intrinsic subtypes.

Evaluation of MR elastography as a response parameter for transarterial chemoembolization of colorectal liver metastases

ObjectiveThe aim of this study was to evaluate magnetic resonance elastography (MRE) as a response parameter in patients who received transarterial chemoembolization (TACE) for the treatment of colorectal liver metastases.Materials and methodsForty-two patients (29 male patients; mean age, 61.5 years; range, 41–84 years) with repeated TACE therapy of colorectal liver metastases underwent on average 2 repetitive magnetic resonance imaging (MRI) and MRE exams in 4- to 6-week intervals using a 1.5-T scanner. MRE-based liver stiffness measurements were performed in normal liver parenchyma and in metastatic lesions. Moreover, the size of the liver metastases was assessed during treatment and compared with the results of the MRE analysis.ResultsLiver metastases showed a significantly higher degree of stiffness compared with the normal liver parenchyma (p < 0.001). However, only a weak correlation was found between the lesion size and stiffness (r = − 0.32, p = 0.1). MRE analysis revealed an increase in stiffness of the colorectal liver metastases from 4.4 to 7.1 kPa after three cycles of TACE (p < 0.001). Also, the mean size of the metastases decreased from 17.0 to 11.3 cm2 (p < 0.001). Finally, the entire liver stiffness increased from 2.9 to 3.1 kPa over the three cycles of TACE therapy.ConclusionIn conclusion, MRE showed a significant change in stiffness and size of liver metastases. Therefore, MRE may provide an added value for an evaluation of treatment response in patients with colorectal liver metastases undergoing TACE.Key Points• MRE showed an increase in stiffness of the colorectal liver metastases during TACE therapy.• Liver metastases showed a significantly higher degree of stiffness compared with the normal liver parenchyma.• However, only a weak correlation was found between the lesion size and stiffness.

Response of Triple-negative Breast Cancer Liver Metastasis to Oral Recombinant Methioninase in a Patient-derived Orthotopic Xenograft (PDOX) Model.

The aim of this study was to establish a patient-derived orthotopic xenograft (PDOX) mouse model of liver metastasis of triple-negative breast cancer (TNBC) and examine the efficacy of oral recombinant methioninase (o-rMETase) on the liver metastasis. TNBC from a patient was implanted in the left hepatic lobe of nude mice to simulate liver metastasis in a PDOX model. Ten days later, all mice underwent laparotomy to measure tumor size and were randomized to three groups: control; o-rMETase 100 U once daily (qd); and o-rMETase 200 U qd. After 9 days of treatment, all mice were sacrificed. At the end of the treatment period for the liver metastasis, the size of liver metastases was 372.6 mm3 in the control group; 160.0 mm3 in the o-rMETase 100 U group; and 245.3 mm3 in the o-rMETase 200 U group. All mice had ascites and 12 out of 14 mice in all groups had mesenteric lymph-node metastasis, as re-metastasis. The mean body-condition score was 1.5 in the control group; 2.4 in the o-rMETase 100 U group; and 2.6 in the o-rMETase 200 U group (control group vs. o-rMETase 200 U group, p<0.05). The TNBC liver metastasis was highly aggressive resulting in re-metastasis and ascites. o-rMETase tended to inhibit the liver metastasis and significantly improved the mouse body-condition score. This new PDOX model of TNBC liver metastasis will be useful for identifying effective agents for this recalcitrant disease.

Prognostic impact of tumour biology compared to surgical margin clearance for colorectal liver metastases in the era of modern chemotherapy and surgery

Background: Historically, microscopically incomplete R1 resections have been associated with increased recurrence and lower survival rates for colorectal liver metastases (CLMs). With advances in chemotherapy, there is a shift towards a more aggressive surgical approach towards liver resection for CLMs. Recent studies have questioned the prognostic significance of obtaining complete surgical margin clearance. This study aims to compare R0 and R1 resections on oncologic outcomes. Methods: From January 2001 to December 2016, all patients who had liver resection for CLM at Singapore General Hospital were analysed retrospectively. Patients with extrahepatic metastases, macroscopic residual tumour and staged liver resections were excluded. Results: Of the 290 patients analysed, 228 (78.6%) and 62 (21.4%) patients underwent R0 and R1 resection respectively. R1 resections were associated with bilobar, multiple and synchronous liver metastases, major liver resections and adjuvant chemotherapy. Independent factors of poor overall and recurrence free-survival were primary colorectal tumour grade, presence of perineural invasion, nodal status, carcinoembryonic antigen (CEA) levels, number and size of liver metastases. R1 resection was likely associated with local intrahepatic recurrence. (HR: 0.74, 95% CI = 0.5 - 1.09, p = 0.122) However, on multivariate survival analysis, it was not an independent predictor for overall and recurrence free survival. Conclusion: Underlying tumour biology is a strong predictor of oncologic outcomes. The prognostic impact of R1 resection should be reviewed given that survival is similar to R0 resection in this current era of chemotherapy.

Plasma KRAS as a biomarker for pancreatic ductal adenocarcinoma (PDAC).

316 Background: PDAC needs validated diagnostic biomarkers for early detection and predictive markers for outcome. As 95% of PDACs harbor KRAS mutations (mKRAS), circulating tumor DNA (ctDNA) has potential utility in PDAC. We assessed the ability to detect and correlate mKRAS in a metastatic PDAC cohort from Memorial Sloan Kettering Cancer Center. Methods: 10 mL of whole blood was collected. cfDNA was extracted with QIAmp or QIAsymphony DNA extraction kits (Qiagen, Valencia, CA). Directed (KRAS G12D, G12R, G12V, Q61H) or multiplex (G12A, G12C, G12D, G12R, G12S, G12V, G13D) digital droplet PCR (ddPCR) was performed with Raindrop Plus (Raindance Technologies, Billerica, MA) or QX200 (BioRad, Hercules, CA) ddPCR systems. Number and size of liver, lung and lymph node metastases, peritoneal disease (mild, moderate, severe), ascites (trace, small, large) and bone mets (Y/N) were assessed by CT scan. Results: See table. 21 (55%) had detectable ctDNA (ctDNA(+)) with mean mutant allele fraction of 4.5% (0.015-36.8). ctDNA (+) vs (-) PFS and OS from collection were 6.9 and 8.4 months vs. 9.9 and 10.5 (p=0.89 for both). CA19-9, PFS and OS did not correlate with ctDNA tertile (p=0.15, 0.54 &amp; 0.50). On treatment and disease activity were not associated with ctDNA status (p= 0.20 &amp; 0.60). Number and size of liver mets were associated with ctDNA (+) (p=0.006 &amp; 0.007). Conclusions: ctDNA KRAS detection was measurable in metastatic disease with rates consistent with other PDAC reports. Median PFS, OS were lower in ctDNA (+) group but not statistically significant in this diverse cohort. Number and size of liver metastases were significantly higher in ctDNA (+). Future study should focus on practice changing applications with standardized collection, intra-patient comparisons and role of liver disease burden. We have initiated studies to evaluate plasma KRAS prior to and during treatment to address its value as a predictive assay and explore factors affecting ctDNA detection. [Table: see text]

Pathological factors and prognosis of resected liver metastases of colorectal carcinoma: implications and proposal for a pathological reporting protocol.

Colorectal cancer is a leading cause of death worldwide. The liver is the most common site of distant metastases, and surgery is the only potentially curative treatment, although the recurrence rate following surgery is high. In order to define prognosis after surgery, many histopathological features have been identified in the primary tumour. In turn, pathologists routinely report specific findings to guide oncologists on the decision to recommend adjuvant therapy. In general, the pathological report of resected colorectal liver metastases is limited to confirmation of the malignancy and details regarding the margin status. Most pathological reports of a liver resection for colorectal liver metastasis lack information on other important features that have been reported to be independent prognostic factors. We herein review the evidence to support a more detailed pathological report of the resected liver specimen, with attention to: the number and size of liver metastases; margin size; the presence of lymphatic, vascular, perineural and biliary invasion; mucinous pattern; tumour growth pattern; the presence of a tumour pseudocapsule; and the pathological response to neoadjuvant chemotherapy. In addition, we propose a new protocol for the evaluation of colorectal liver metastasis resection specimens.

Abstract CT109: HITM-SIR: Phase Ib trial of CAR-T hepatic artery infusions and selective internal radiation therapy for liver metastases

Abstract OBJECTIVES: There are no effective treatment options for patients with unresectable CEA+ liver metastases (LM) from gastrointestinal adenocarcinoma refractory to conventional systemic therapy. In the previous Hepatic Immunotherapy for Metastases (HITM) phase I study we demonstrated the safety and biologic activity of anti-CEA CAR-T cell hepatic artery infusions (HAI). HITM-SIR was a single arm phase Ib trial testing anti-CEA CAR-T HAI followed by selective internal radiation therapy (SIRT) in patients with refractory CEA+ LM. METHODOLOGY: We enrolled 8 patients with unresectable, chemotherapy refractory CEA+ LM and 6/8 completed the study. Two patients were withdrawn for disease progression prior to CAR-T infusion and biliary obstruction due to centrally located disease. Limited extrahepatic disease (EHD) was permitted. Subjects received 3 HAI of anti-CEA CAR-T cells (1e10 cells per dose) along with low dose continuous IL-2 infusions (50,000 IU/kg/day). SIRT was administered in standard fashion 2 weeks following the 3rd CAR-T HAI. Primary objective was to establish safety of the CAR-T/SIRT combination. Secondary objectives included response assessed by modified RECIST (mRECIST), immune-related response criteria (irRC), and tumor marker kinetics. RESULTS: The mean age for enrolled subjects was 54.6 years (39-61) with 3 women and 5 men. Histologies (completed patients): 2 colon, 2 rectal, and 2 pancreas. This heavily pre-treated, advanced disease group of patients received an average of 2.3 lines of prior chemotherapy, 3/6 had &amp;gt;10 LM, and the average largest LM size was 7.3 cm. The average transduction efficiency as measured by CAR expression was 60.4%, with 90.9% viability, and an average production time for &amp;gt;3e10 cells of 13.8 days. There were no grade (G) 4/5 events related to the CAR-T, SIRT, or combination. Toxicities included G 1/2 liver function test elevations (n=5/6), fever (n=5/6), hypereosinophilia (n=2/6), and edema (n=2/6). G3 toxicities included colitis (n=2/6), fever (n=2/6), and edema (n=2/6). One patient experienced a hypertensive crisis during a single CAR-T infusion but tolerated 2 infusions without incident. All colitis episodes resolved with IL-2 dose reductions. Post-SIRT serum CEA decreases were noted in 2/6 patients (-40% and -71%) with CA19-9 decreases in 2/5 detectable patients (-31% and -32%). When considering all on-study time points, 5/6 patients had CEA responses (mean decrease 59.7%) and 4/5 patients expressing CA 19-9 decreases (mean 59.6%). At completion of the study, 3/6 patients had stable disease (SD) in the liver by mRECIST and irRC, and 3/6 SD overall by irRC. Target liver lesion decreases in size among patients with SD ranged from 6-28%. Regression of extrahepatic tumors or abscopal effects were noted in 2/6 at lung and bone sites. One patient remains without evidence of viable liver disease at 10.8 months follow-up. The median overall survival time for all patients is 6.9 months (range 3.8-10.8+). CONCLUSIONS: Following this phase Ib trial, the recommended phase 2 dose for anti-CEA CAR-T HITM infusions is 1010 cells with or without SIRT. The favorable safety profile and evidence of biologic activity indicate that CAR-T HITM infusions should be further studied in a phase 2 trial. Clinical trial information: NCT02416466. Citation Format: Steven C. Katz, Ethan Prince, Marissa Cunetta, Prajna Guha, Ashley Moody, Vincent Armenio, Li J. Wang, N. Joseph Espat, Richard P. Junghans. HITM-SIR: Phase Ib trial of CAR-T hepatic artery infusions and selective internal radiation therapy for liver metastases [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 CT109. doi:10.1158/1538-7445.AM2017-CT109